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Pharmacology is the study of drugs and their action on the body. A drug can be broadly defined as any man-made, natural, or endogenous molecule which exerts a biochemical and/or physiological effect on the cell tissue organ or organism It is the study of the

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and/or physiological effect on the cell, tissue, organ, or organism. It is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. Any substance that has medicinal properties, is considered a pharmaceutical.

Pharmacology encompasses drug composition and properties, synthesis and drug design, molecular and cellular mechanisms, organ/systems mechanisms, signal transduction/cellular communication, molecular diagnostics, interactions, toxicology, chemical biology, therapy, and medical applications and antipathogenic capabilities.

Medicinal chemistry encompasses synthetic organic chemistry and aspects of natural products and computational chemistry in close combination with chemical biology, enzymology and structural biology, together aiming at the discovery and development of new therapeutic agents. It involves chemical aspects of identification, and then systematic, thorough synthetic alteration of new chemical entities to make them suitable for therapeutic use. It includes understanding their structure-activity relationships (SAR). Pharmaceutical chemistry is focused on quality aspects of medicines and aims to assure fitness for purpose of medicinal products.

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Medicinal chemistry interfaces biology and chemistry and is a highly interdisciplinary. It places organic, physical, and computational chemistry alongside biochemistry, molecular biology, pharmacognosy and pharmacology, toxicology and veterinary and human medicine. It also requires business aspects, including project management, statistics, and pharmaceutical business practices, systematically oversee altering identified chemical agents such that after pharmaceutical formulation, they are safe and efficacious, and therefore suitable for use in treatment of disease.

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Some of the things the body can do to a drug.

The two main areas of pharmacology are pharmacodynamics and pharmacokinetics.

Pharmacodynamics studyies the effects of the drug on biological systems. Pharmacodynamics examines the interactions of the chemicals with the biological receptors,

Pharmacokinetics studies the effects of biological systems on the drug. Pharmacokinetics examines the absorption, distribution, metabolism, and excretion (ADME) of chemicals from the biological systems

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biological systems.

Pharmacology is not synonymous with pharmacy.

Pharmacology, a biomedical science, deals with the research, discovery, and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals.

Pharmacy is a health services profession concerned with application of the principles learned from pharmacology in its clinical settings; whether it be in a dispensing or clinical care role.

Metabolism (Greek: "change") is the set of life‐sustaining chemical transformations within the cells of living organisms.Three main purposes of metabolism are:

1. the conversion of food/fuel to energy to run cellular processes, 2. the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some

Metabolism is a constant battle of life and death.

for proteins, lipids, nucleic acids, and some carbohydrates, and 3. the elimination of nitrogenous wastes. 

These enzyme‐catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transport of substances into and between different cells.

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Metabolism is usually divided into two categories:

1. catabolism, the breaking down of organic matter, for example, by cellular respiration, and 2. anabolism, the building up of components of cells such as proteins, lipids, carbohydrates and nucleic acids.  Usually, breaking down releases energy and building up consumes energy.

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http://www.nature.com/nrc/journal/v16/n10/full/nrc.2016.77.html

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?Nature Reviews Cancer Volume: 16, Pages:635–649 Year published:(2016) DOI:doi:10.1038/nrc.2016.77 Published online 16 September 2016

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Examples of various types of medicines 1 For the gastrointestinal tract (digestive system)2 For the cardiovascular system

Drug (Medicine) - a natural or artificial substance given to treat or prevent disease or to lessen pain, a substance other than food (?) that causes a physiological change in the body, use can be short term (acute problems) or regular (chronic problems) Drugs are classified in various ways. All drugs have some side effects and can possibly lead to addiction.

Almost any chemical can affect a living organism. A h i l th t

Chapter 1 - Drugs and drug targets: an overview

2 For the cardiovascular system3 For the central nervous system4 For pain and consciousness (analgesic drugs)5 For musculo-skeletal disorders6 For the eye7 For the ear, nose and oropharynx8 For the respiratory system9 For endocrine problems10 For the reproductive system or urinary system11 For contraception12 For obstetrics and gynecology

Any chemical that canaffect the body is, in a sense, a "lead" compound. The more we know how a drug works (its mechanism of interaction) the better we can direct its usefulness and control its side effects.

These are our biological

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12 For obstetrics and gynecology13 For the skin14 For infections and infestations15 For the immune system16 For allergic disorders17 For nutrition18 For neoplastic disorders (tumors, benign or malignant)19 For diagnostics20 For anesthesia21 For euthanasia

biologicalcomponents. Each is incredibly complicated, separately and together (blood, nerves, lymph, immunity, etc.)

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S

O

NH2HN

HO

OC03CA01

Anatomical Therapeutic Chemical Classification System (ATC) - assigns ATC code = an alphanumeric code that assigns a drug to a specific class. Code = jargon, language of experts, not a common language of everyday people.

First levelThe first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:

A Alimentary tract and metabolism B Blood and blood forming organs C Cardiovascular system D Dermatologicals G Genito-urinary system and sex hormones H Systemic hormonal preparations, excluding sex hormones and insulins J Antiinfectives for systemic use

Furosemide (Lasix) used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It has also been used to prevent and treat race horses for exercise-induced pulmonary hemorrhage.

O

ClO

J Antiinfectives for systemic use L Antineoplastic and immunomodulating agents M Musculo-skeletal system N Nervous system P Antiparasitic products, insecticides and repellents R Respiratory system S Sensory organs V Various

Example: C Cardiovascular systemSecond levelThe second level of the code indicates the therapeutic main group and consists of two digits.Example: C03 Diuretics

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Example: C03CA01 Furosemide

Third levelThe third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.

Example: C03C High-ceiling diureticsFourth levelThe fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.Example: C03CA SulfonamidesFifth levelThe fifth level of the code indicates the chemical substance and consists of two digits.

A: alimentary tract and metabolism

Food and Beverages go in at the top and...

We are like a big stack of donuts.

How can something on the inside really be something on the outside. Surface area outside = 20

nutrientsbacteriavirusesfungiparasites

intestines

m2, inside = 400 m2.

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...waste products come out at the end.

The intestinal epithelium is the layer of cells that forms the luminal surface or lining of both the small and large intestine (colon) of the gastrointestinal tract. It is composed of simple columnar epithelium. It has two important functions: absorbing helpful substances and providing a barrier against harmful substances. Our gut has trillions of bacteria (and other microorganisms).

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C: cardiovascular system

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Drugs can be differentiated by:

How they are administered - consumed (liquid or solid by stomach or intestines), dissolved under tongue or in eyes, injected, inhaled, absorbed (patch, cream or ointment), insufflation (snorted), rectally (as a suppository), vaginally

Sources – plants, whole or parts (herbs and spices from stems, leaves, flowers, roots) or extracted substances (about 70% of pharmaceutical drugs come from naturalor extracted substances (about 70% of pharmaceutical drugs come from natural products), organic synthesis (vast topic), synthesis by microorganisms (alcohol by yeast, penicillins, cephlosporins, cyphamycins, cyclosporins by fungi = yeast/molds, etc.), toxins (snakes, spiders, frogs, insects, puffer fish, algae red tides, etc.), genetically modified bacteria or yeast (to synthesize human insulin), animals (bovine or porcine insulin, Premarin as Hormone Replacement Therapy from horse urine, blood thinning drug called ATryn, is made in the milk of genetically altered goats).

Often regulated into 3 categories::

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Often regulated into 3 categories::over the counter (OTC) available in supermarkets without any restrictions, behind the counter (BTC) can be dispensed by a pharmacist without doctor's prescriptionprescription only medicine (POM) prescribed by licensed pharmacist (a doctor)

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Shape and polarity control almost everything in chemistryIt can be simple and it can be complex

Simple shapes: sp, sp2, sp3 (C, N, O, S, P, etc.)

Simple polarity: ionic polar (and H bonds) dispersion

CO O carbon dioxide

linear

boron trifluoride

trigonal planar

B F

F

F

P

O

OO

Ophosphate

tetrahedral

Types of Shapes

Simple polarity: ionic, polar (and H bonds), dispersion(sugars, amino acids, fatty acids, nucleic acids)

Complex shapes: infinite variety (molecules, polymers)

Complex polarity: infinite variety(carbohydrates, proteins, lipids, DNA & RNA)

FF P

F

FF

phosphorouspentafluoride

trigonal bipyramidal

F

F

F

F

S

F

F

sulfurhexafluoride

octahedral

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Types of Polarity

ionic sodium chloride

Na Cl

bp = 1413oCmp = 801oC

= ?

C

O

H3C Hdipolesethanal

bp = +20oCmp = -123oC = 2.7 D

H3C

H2C

OH

hydrogen bondingethanol

bp = +78oCmp = -114oC = 1.7 D

HO

H

hydrogen bondingwater

bp = +100oCmp = 0oC = 1.8 D

C

O

H Hdipoles

methanal

bp = -19oCmp = -92oC = 2.3 D

Ba+2 O-2

ionicbarium oxide

bp = 1923oCmp = 2000oC

= ?

C

C

H3C H

bp = -104oCmp = -169oC = 0 D

C

C

H Hdispersion

forcesethene

bp = -161oCmp = -182oC = 0 D

C

H

HH

H

HH H H

dispersionforces

methane

dispersionforces

propenebp = -48oC

mp = -185oC = 0.4 D

The acceptor binding region of vertebrate UGT proteins. Shown is an alignment of the acceptor binding region of the human UGT1 and UGT2 proteins. Comparisons were made among human, chimpanzee, rhesus monkey, baboon, dog, mouse, rat, chicken, and zebrafish.

Complex shapes: infinite variety (molecules, polymers)

Complex polarity: infinite variety(carbohydrates, proteins, lipids, DNA & RNA)

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(ionic, dipoles, H bonds, dispersion forces)

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n = 1

+1 +2

shielding = 0

Ztotal = 1

Zeffective = 1

H He

shielding = 0

Ztotal = 2

Zeffective = 2

Lin 2 B B C N O F N

Atomic attraction for electrons(Where does polarity come from?)

Attractions are stronger across a row because the effective nuclear charge is larger.

valence electrons = bonding electrons (attracted by Zeffective)core electrons = full inner shells that shield Ztotal

Review Topics: Polarity and Shape control the chemistry. Full shells (or subshells)This is the goal.

radius = 52 pm radius = 31 pm

+3

Li

shielding = -2Ztotal = 3

Zeffective = 1

n = 2

+4

Be

+5

B

+6

C

+7

N

+8

O

+9

F

+10

Ne

shielding = -2Ztotal = 4

Zeffective = 2shielding = -2

Ztotal = 5

Zeffective = 3

shielding = -2Ztotal = 6

Zeffective = 4shielding = -2

Ztotal = 7

Zeffective = 5shielding = -2

Ztotal = 8

Zeffective = 6shielding = -2

Ztotal = 9

Zeffective = 7shielding = -2

Ztotal = 10

Zeffective = 8

Cl Arn = 3

Att ti t

Na

radius = 167 pm radius = 112 pm radius = 87 pm radius = 67 pm radius = 56 pm radius = 48 pm radius = 42 pm radius = 38 pm

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+17 +18

shielding = -10

Ztotal = 17

Zeffective = 7

shielding = -10Ztotal = 18

Zeffective = 8

Attractions are strongerup a column because the valence electrons are closer to the same effective nuclear charge.

+11

shielding = -10

Ztotal = 11

Zeffective = 1radius = 190 pm radius = 79 pm radius = 71 pm

K (243 pm)Cs (298 pm)

Br (94 pm)I (115 pm)

Kr (88 pm)

Xe (108 pm)other radii

other radii

Volume of electron cloud compared to volume of nucleus

VeVn

43 (1.33)(3.14)(100,000)3 = 4 x 1015= =

electron clouds determine the overall volumeof atoms

mass protonsmass electrons

18001

protons and neutronsdetermine an atom's mass=

ecore evalence

p,n

nucleus

rern

3

mpme

=

1

100,000

p = protons = constant # that defines the elementn = neutrons = varies = defines the isotopee = electrons = varies, depending on bonding patterns associated termif electrons = protons (same # of e's and p's) atomif electrons < protons (deficiency of e's) cationif electrons > protons (excess of e's) anion

(eval) = valence electrons = The outermost layer of electrons, which determines the bonding patterns. The usual goal is to attain a noble gas configuration. This is accomplished by losing e's (forming cations) or gaining e's (forming anions) or sharing e's (covalent bonds)

5 feetvs.

100 miles

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( g ) g g ( g ) g ( )

(ecore) = core electrons = The innermost layer(s) of electrons (usually full shells or subshells). These e's are held too tightly for bonding (sharing) and not usually considered in the bonding picture. These e's cancel a portion of the nuclear charge (called shielding) so that the valence e's only see part of the nuclear charge, called Zeffective.

Zeffective = (# protons) - (core e's) = the effective nuclear charge. This is the net positive charge felt by the valence e's (bonding and lone pairs). Zeffective = same # as the column of the main group elements.

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H1

+1

+1

shell = Ztotal =

core e- =Zeffective =

0

He

1+2

+20

Atoms (valence shell, Ztotal, core electrions = shielding, Zeffective)

C N O F

shell = Ztotal =

core e- =Zeffective =

2

+6

+4

2

+7

+5

2

+8

+6

2+9

+72 2 2 2

Ne

2

+10

+8

2

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Si P S Cl

shell = Ztotal =

core e- =Zeffective =

3

+14

+4

3+15

+5

3

+16

+6

3

+17

+710 10 10 10

Ne

3+18

+8

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Electronegativity, (chi), is the property that indicates an atoms attraction for electrons in chemical bonds with other atoms.

H = 2.2Li = 1.0 Be = 1.5 B = 2.0 C = 2.5 N = 3.0 O = 3.5 F = 4.0 Na 0 9 Mg 1 2 Al 1 5 Si 1 9 P 2 2 S 2 6 Cl 3 2

Approximate electronegativity values for some main group elements.(atoms in red have some biological significance)

Group 1AZeff = +1

Group 2AZeff = +2

Group 3AZeff = +3

Group 4AZeff = +4

Group 5AZeff = +5

Group 6AZeff = +6

Group 7AZeff = +7

Group 8AZeff = +8

He = noneNe = noneA

V Cr Mn Fe

1 65 1 90Co Ni Cu Zn

Na = 0.9 Mg = 1.2 Al = 1.5 Si = 1.9 P = 2.2 S = 2.6 Cl = 3.2 K = 0.8 Ca = 1.0 Ga = 1.6 Ge = 2.0 As = 2.2 Se = 2.5 Br = 3.0 Rb = 0.8 Sr = 0.9 In = 1.8 Sn = 2.0 Sb = 2.0 Te = 2.1 I = 2.7

Simplistic estimate of bond polarities using differences in electronegativity between two bonded atoms.

0.4 0.4 < < (1.4 - 2.0)(1.4 - 2.0) <

considered to be a pure covalent bond (non-polar)considered to be a polar covalent bond (permanent charge imbalance)considered to be an ionic bond (cations and anions)

3d elements4d elements

BA A B =bond polarity based on

Ar = noneKr = 3.0Xe = 2.6

1.65-1.90

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FHMgBr Br

Br =

=

Mg

= 1.8

F =

=

H

= 1.8TBP = 711oC(ionic salt)

TBP = 20oC(molecular)

Rules can be ambiguous.

CuI (TBP = 1290oC NH3 (TBP = -33oC

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1. Dispersion forces / van der Waals interactions / London forces (nonpolar attractions)

Dispersion forces are temporary fluctuations of negative electron clouds from one direction to another, relative to the less mobile and more massive positive nuclear charge. These fluctuations of electron density induce fleeting, weak dipole moments. Polarizability is the property that indicates how well this fluctuation of electron density can occur about an atom.

In a nonpolar molecule the and are centered, on average This would seemaverage. This would seem to indicate that in nonpolar molecules there is no polarity or attraction between molecules. So why do such substances liquify and solidify? Why aren't they always gases?

+ - + -

and are not centered creating tempory polarity.

Fast moving electrons shift position relative to slow moving nuclei, creating a temporary imbalance of charge,

Dispersion Forces

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+Z +Z +Z +Z

Weak, fluctuating polar forces of attraction between molecules.

p y g

which induces a similar distortion of the electron clouds in neighbor structures and a weak attraction for neighbor molecules.

+Z = nuclear protons = electron cloud

Zeff = +4 Zeff = +5 Zeff = +6 Zeff = +7

C N O F

Periodic trends in polarizability, .

F is like a marble.

Cl

Br

Zeff = +7

Z 7

Polarizability is greater because there is a weaker hold on the electrons because they are farther away from the same effective nuclear charge, so they are more easily

Features that increase polarizability:

1. smaller Zeff, favors C > N > O > F

Polarizability is larger with smaller Zeff because the electrons are not held as tightly, so they are more easily distortable.

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I

Zeff = +7

Zeff = +7

y ydistortable.2. valence electrons farther from the

nucleus when Zeff is similar I > Br > Cl > F.

I is like a cotton ball.

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10

200

150

250

I2bp

The halogen molecules are similar in shape and nonpolar. There is a smooth, increasing trend in both melting and boiling points. This is suggestive of some factor increasing the forces of attraction between molecles of the halogen family as they get larger. The smooth trend in melting point is not typical, because it can vary so much with differences in shapes. The even change in melting points is observed here because the halogen molecules all have a similar, rigid shape.

Phase at room temperatureF2 = gas He = gasCl2 = gas Ne = gasBr2 = liquid Ar = gasI2 = solid Kr = gas

Temp. (oC)

100

50

0

-50

-100

150

Cl2

Br2

mp have a similar, rigid shape.

The Noble gas molecules are similar in shape and nonpolar. There is a smooth, increasing trend in both melting and boiling points. This is suggestive of some factor increasing the forces of attraction between molecles of the halogen family as they get

room temp 25oC

XX

Xe

bpmp

A A A

1 atom vs. 2 atoms

A A A

19

-150

-200

-250

F2

-273 absolute zero = 0 KHeNe

ArKr

between molecles of the halogen family as they get larger. The smooth trend in melting point is not typical, because it can vary so much with differences in shapes. The even change in melting points is observed here because the halogen molecules all have a similar, spherical shape.

H2

Xe

Dispersion forces are cumulative, so when the contact surface area is larger, the interactions are stronger (because there are more of them). Higher molecular weight alkanes have more carbon atoms to interact than lower molecular weight alkanes (even though only similar weak dispersion forces are present in both).

Alkane boiling pointmethane, CH4 -162 ethane, C2H6 -89 73propane, C3H8 -42 47butane, C4H10 0 42pentane, C5H12 36 36hexane, C6H14 69 33h t C H 98 29

Alkane boiling pointtridecane, C13H28 235tetradecane, C14H30 254pentadecane, C15H32 271hexadecane, C16H34 287heptadecane, C17H36 302octadecane, C18H38 316

d C H 330

CH4

CH3CH2CH2CH2CH2CH3

CH4 Larger molecules have more contact surface area with neighbor molecules. Greater dispersion forces

From the examples above, you can see that even the weak dispersion forces of attraction become significant when a large number of them are present.

(x1)

heptane, C7H16 98 29octane, C8H18 126 28nonane, C9H20 151 25decane, C10H22 174 23undecane, C11H24 196 22dodecane, C12H26 216 20

nonadecane, C19H40 330icosane, C20H42 343henicosane, C21H44 356doicosane, C22H46 369tricosane, C23H48 380 triacotane, C30H62 450tetracotane, C40H82 563

CH3CH2CH2CH2CH2CH3

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3

Greater dispersion forces mean a higher boiling point.

150

200 250

300

350 Boiling PointTemp (oC)

Easy to compare because they are all linear.

(x6)

(x12)

20

-150

-100

-50

0 50

100

150

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20

Straight chain alkanes

bp of water

mp of water

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In alkane isomers (having the same number of atoms, CnH2n+2), more branching reduces contact with neighbor molecules and weakens the intermolecular forces of attraction. Linear alkanes have stronger forces of attraction than their branched isomers because they have a greater contact surface area with their neighbor molecules. Branches tend to push neighbor molecules away. The strength of these interactions falls off as the 6th power of distance. A structure twice as far away will only have 1/64 the attraction for its neighbor.

More atoms increase the contact surface area with neighbor

Less branching increases contact surface area with neighbor

H2CH3C

H2CH3C

H2C CH3

CH

CH3

H3C CH3bp = -42oC bp = -0.5oCbp = -12oC

CH3 11

1

12

164

=

=

6

6

H2CH3C

H2C CH3

bp = -0.5oC

referencedistance

gmolecules (not isomers).

surface area with neighbormolecules in these isomers.

150oC

100oC

50oC

Temp(oC)

More efficient packing in lattice structure due to compact rigid shape = closer contact(higher mp).

bp = +106mp = +101

bp = +126

Stronger dispersion forces because of greater surface contact area in linear chain (higher bp).

100oC boiling point

hot dog?

your finger?T = 75oC

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solid lattice, fixed, close positions

meltingpoint

liquid, mobile, close positions

boilingpoint

0oC

-50oC mp = -57

25oC room temp water

freezing point0oC

gas, mobile, separated, PV=nRT

far apart( no interaction)larger

energysmallerenergy

C

H

HH

C

H

H

H

CH C H CbCa

H

H

Ca

ethanetetrahedral carbon atoms

ethenetrigonal planar carbon atoms ethyne

linear carbon atoms

allenetrigonal planar carbon atomsat the ends and a linear

C CH H

H H

H

H

Hybridization explains the shapes we observe in organic and biochemistry.

sp3 sp2sp sp2 sp sp2

HCH bond angles 109o HCC bond angles 109o

HCH bond angles 120o (116o)CCH bond angles 120o (122o)

linear carbon atoms

HCC bond angles = 180o

carbon atom in the middle

HCaH bond angles 120o HCaCb bond angles 120o

CaCbCa bond angles = 180o

C

H

HN

H

H

CH N CbCa

H

NC NH H

H

H

Lone pairs can occupy a similar space to a bonded atom. (Zeff(C) = +4, Zeff(N) = +5, Zeff(O) = +6)

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HH

H

C

H

HH

O

H

C OC OH

HCO O

carbon monoxide

methanimine

methanol methanal

methanamine hydrogen cyanide

carbon dioxide

ethenimine

Which electrons are held tighter, lone pair electrons or bonded electrons?

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HH HH

CH2C CH2

H

allylic carbocation(2D and 3D structures)

CH2C O

H

HH HH

enolate anion(2D and 3D structures)

CH2C CH2

H

CH2C O

H

Resonance occurs through parallel p orbitals and stabilizes positive charge, negative charge, free radicals and neutral conjugated pi systems.

C C

H

H

C H

H

H

C C

H

H

C H

H

H

CH2C CH2

H

allylic free radical(2D and 3D structures)

C C

H

H

O

H

C C

H

H

O

H

C CH2H2C

H

bezene resonance(2D and 3D structures)

equivalentstructures

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C C

H

H

C H

H

H

C C

H

H

C H

H

H

2

C C

C

CC

CH H

H

H H

H

C C

C

CC

CH H

H

H H

H

2a. Dipole-dipole interactions (in between polarity) - Dipole moments are less than full charges and the bonds are very directional (not "omni"), so attractions for neighbor molecules are weaker than is found in ionic salts. However, polar molecules usually have stronger attractions than nonpolar molecules of similar size and shape. Boiling points are a better indication of the strength of attractions among neighbor molecules than melting points (when other factors are similar). A higher boiling point indicates stronger attractions. Molecular dipole moments are indicators of charge imbalance due to a difference in electronegativity , bond length and molecular shape.

OCH H

nonpolar polar

O

more polar

CH H

electron proton

CH H

CH H = 0.0 Dbp = -104oCmp = -169oCH2O sol. = 2.9mg/LpKa = 44

= 2.3 Dbp = -20oCmp = -92oCH2O sol. = 400g/LpKa = NA

CH H

resonanceTbp = 84oCC

H H

versus

C

O

H H

Hpolarnonpolar

N

more polarC

H

N

= (q)x(d) = dipole momentq = charged = distance

0.208A

= 1.0 Debye

proton

bondCH3-X (D) d(pm) energyCH3-F 1.85 138.5 461CH Cl 1 87 178 4 356

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CC

H

CN

H

= 0.0 Dbp = -81oCmp = -84oCH2O sol. = insolublepKa = 25

= 2.98 Dbp = +26oCmp = -13oCH2O sol. = misciblepKa = 9.2

CN

H

resonance

Tbp = 107oC

CH

CH

versus

CH3-Cl 1.87 178.4 356CH3-Br 1.81 192.9 297CH3-I 1.62 213.9 239

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CC

H3C

CN

H3C

H polarnonpolar

= 0.78 Dbp = -23oC

o

= 3.92 Dbp = +81oC

o

CN

H3C

more polar

resonance

Tbp = 104oCC

CH

CN

H3C

versus

What is the effect of "R" groups? Do they make the molecule more polar, less polar or no different? Electron donation or electron withdrawal through sigma bonds is called an inductive effect.

mp = -102oCH2O sol. = insoluble

mp = -46oCH2O sol. = miscible

CH3C

C

O

H H

= 2.3 Dbp = -20oCmp 92oC

polar

C

O

H H

resonanceC

O

H3C H

= 2.68 Dbp = +20oC

C

O

H3C CH3

= 2.91 Dbp = +56oC

C

O

H3C H

resonanceC

O

H3C CH3

resonancepolar polar

25

mp = -92oCH2O sol. = 400g/L

mp = -123oCH2O sol. = very sol.

mp = -94oCH2O sol. = very sol.

CH

H

H

CH3C

H

H

CH3C

H

CH3

CH3C

CH3

CH3

C O

H

HH

C O

H3C

HH

C O

H3C

HH3C

C O

H3C

H3CH3C

Is the conclusion above consitent with the following observations?

G = 315 kcalmole G = 270 kcal

mole G = 250 kcalmole G = 230 kcal

mole pKa = 15.5 pKa = 15.9 pKa = 17.1 pKa = 19.2

2b. Hydrogen bonds - Hydrogen bonds represent a very special dipole-dipole interaction. Molecules that have this feature have even stronger attractions for neighbor molecules than normal polar bonds would suggest. Solvents that have an O-H or an N-H bond are called "protic solvents" and can both donate and accept hydrogen bonds (because they also have lone pairs of electrons). They generally have higher boiling points than similar sized structures without any "polarized hydrogen atoms". We call such interactions "hydrogen bonds". A molecule that has such a polarized hydrogen is classified as a hydrogen bond donor. A molecule that has a partial negatively charged region that can associate with such a hydrogen is classified as a hydrogen bond acceptor.

O

HH

O

H

H

donates

accepts hydrogen bond

Hydrogen bonding holds the molecules more tightly to one another. This can be seen in higher boiling points among similar structures where hydrogen bonding is possible versus not possible. Many examples O H

OH

H

donates hydrogen bond

g p p y pbelow show this property.

Cl

H

CH3C

O

O H

C CH3

O

OH

CCH3C

H

H

H

accepts hydrogen bond

donates hydrogen bond

donates hydrogen bond

accepts hydrogen bond

C

O

H3C CH3

OH

H

H

accepts hydrogen bond

donates hydrogen bond

Hth h d b d i G C b i two hydrogen bonds in A T base pair

26

N

N

N

N

N H

H

O

HDNA

N

N

NH

H

O DNA

guanine cytosine

three hydrogen bonds in G-C base pair

N

N

N

N

DNAN

N

O

O DNAadenine thymine

two hydrogen bonds in A-T base pair

H

N H

H

Which base pair binds more tightly, GC, AT or are they about the same?

4/3/2017

14

Provide an explanation for the different boiling points in each column.

HFbp = +20oCmp = -84oC = 1.86 D = 1 8

H2O

bp = +100oCmp = 0oC = 1.80 D = 1 2

NH3

bp = -33oCmp = -78oC = 1.42 D = 0 8

CH4

bp = -164oCmp = -182oC = 0.0 D = 0 3

4B 5B 6B 7B

Hebp = -269oCmp = -272oC = 0.0 D = NA

8B

Temp(oC)

100

50

0

boiling points (oC)H2O

HFH2Te = 1.8

bp = -85oCmp = -114oC = 1.0 D = 1.0

bp = -67oCmp = -87oC = 0.8 D = 0.8

= 1.2

bp = -60oCmp = -82oC = 1.0 D = 0.4

bp = -41oCmp = -66oC = ? D = 0.4

= 0.8

bp = -88oCmp = -132oC = 0.0 D = 0.0

bp = -62oCmp = -111oC = 0.0 D = 0.0

= 0.3

bp = -112oCmp = -185oC = 0.0 D = 0.3

bp = -88oCmp = -165oC = 0.0 D = 0.2

HClH2SPH3

SiH4HBrH2SeAsH3

GeH4

NA

bp = -246oCmp = -249oC = 0.0 D = NA

bp = -185oCmp = -189oC = 0.0 D = NA

Ne

Ar

0

-50

-100

-150CH4

GeH4

SiH4

SnH4

SbH3

PH3

NH3

-200

-250H

H2S

H2Se

HCl HBr

HI

Ne

Ar

Kr

AsH3

b 35oCHIH2TeSbH3SnH4

b 153oCKr

27

row2

row3

row4

row5

-300

Hebp = -35oCmp = -51oC = 0.4 D = 0.5

bp = -2oCmp = -49oC = ? D = 0.1

bp = -17oCmp = -88oC = 0.0 D = 0.2

bp = -52oCmp = -146oC = 0.0 D = 0.2

bp = -153oCmp = -157oC = 0.0 D = NA

Column shifted down one row.

H3C

H2C

CH3 H3CO

CH3

= 0.08 Dbp = 42oC

= 1.30 Dbp = 22oC

Offer explanations for the following observations.

H3C

H2C

O

= 1.69 Do

H

= 20oC = 100oCbp = -42 Cmp = -188oCH2O sol. = 0.004 mg/L

bp = -22 Cmp = -141oCH2O sol. = 71g/L

bp = +78oCmp = -114oCH2O sol. = miscible

20 C = 100 C

CH2

H2C

CH2

CH2

OCH2

H3C CH3H3C CH3

CH2

H2C

CH2

H3C OH

= ? D = 1.15 D = 1.66 D

28

bp = +36oCmp = -130oCH2O sol. 0 mg/L

bp = +35oCmp = -116oCH2O sol. = 69 g/L

bp = +118oCmp = -90oCH2O sol. = 73 g/L

= -1oC = 83oC

Perhaps, polarity is buried inside nonpolar covering. Holds back dispersion forces with neighbor molecules.

4/3/2017

15

The types of interactions between molecules depends on functional groups and solvation. Organic functional groups are mostly similar to biochemical functional groups.

CR

O

OC

R

O

OC

R

O

Cl

CR

O

OR

O

C

O

R

H

anhydridescarboxylic acids esters acid chlorides

CR

O

SR

thioesters

CR

O

N

CR N

OR

H

OR

R

SR

H SR

R

CR

O

HC

R

O

R

NR O

XRNR

H

X = F, Cl, Br, I

H

H

amides (1o, 2o, 3o)nitriles aldehydes ketones alcohols

29

CR C H

SR

NR O

O

CC

H

H

H

R

H

thiols ethersthioetherssulfides

halogencompounds

nitro compounds

nitroso compounds

alkenes alkynes aromatic heteroaromatic

amines (1o, 2o, 3o)

NThere is chemical logic for all of these functional groups. You have to understand how they react to plan strategies in drug design.

HN O S

aziridine oxiraneethylene oxide

thiiraneepisulfide

HN

azetizine

O

oxetane

S

thietane

HN O S

HN O S

HN O O

heterocycles are common in biochemistry and medicinal chemistry

pyrrolidine tetrahydrofurane(THF)

tetrahydrothiophene pyrrole furane thiopheneNimidazole

N

oxazole

N

isoxazole

HN

i idi

N

idi

O

t t h d

O S

thiane

S

thiop rane

30

piperidine pyridine tetrahydropyrane pyrane thiane thiopyrane

NH

HN

piperazine

O

HN

morpholine

O

O

dioxane

O

O

dioxane

N

N

N

N

pyrimidinepyrazine

N

N

purine

N

NH

1

2

3

4

56

7

8

91

2

3

4

5

6

4/3/2017

16

O

OH

OHHO

HO

HO

OH

O

OHHO

HO

HO

aldose

O

OH

OHHO

O

HO

O

OHHO

HO

HO

hemi-acetal

acetal

HO

pyranoseOH

Biochem structures are more like names of your classmates. Every one has to be learned individually. (* = chiral center). Stereochemistry is critical part of each structure.

*

*

* *

*

*

**

*

24 stereoisomers25 stereoisomers

*

*

* *

*

*

*

* *

*

210 stereoisomers and multiple ways to attach

OH

OH

OHO

HO

ketonse

O

OH

OHHO

O

hemi-ketal ketal

O OH

OH

OHHO

HO

furanose

O

OH

OH

HO

HO

glycosides

N N2

34

8

9

H

N

H

1

25

N

N N2

34

8

9

H

N N2

34

8

9

H

H2N

*

*

*

*

* *

*

p y

**

**

*

*

* *

*

23 stereoisomers 24 stereoisomers

29 stereoisomers and multiple ways to attach

31

NN

N

N

15

6 7N

purine

pyrimidine

imidazole

N

NH

O

NH2

cytosine

HN

NH

O

O

thymine uracil

3

4

HN

NH

O

O

NN1

56 7

adenine

HNN

156 7

guanineNH2 O

H2NC

C

HR

O

OHamino acids(20 essential,

there are 100s of others)

12

34

5

6

steriodshormonesproteinsfatty acidsglyceridesneurotransmittersand on and on...

S

C

H OH

H

glycoaldehyde

O H

achiral

aldehyde carbohydrates (3C, 4C, 5C, 6C, more?)

C

H OH

CH2OH

D-glyceraldehyde

O HC

HHO

CH2OH

OH

L-glyceraldehyde

R

Rtop

H OH

CH2OH

generic carbohydrate

When the second to the last "OH" is on the right side, biochemists refer to it as a "D" carbohydrate. Most carbohydrates in nature are "D". Most amino acids, on the other hand are "L" with a "NH2" on the left side.

CO2H

H2N H

R

generic amino acid

D L

C

H OH

D-erythrose

O H

D-threose

H

CH2OH

OH

C

HHO

OH

H

CH2OH

HO

C

HO H

O H

H

CH2OH

OH

L-erythrose

C

OHH

OH

H

CH2OH

HO

L-threose

Biochem names are all different. Organic names are easier. All of these are 2,3,4-trihydroxybutanal.

1 = (2R,3R)-2,3,4-trihydroxybutanal2 = (2S,3S)-2,3,4-trihydroxybutanal3 = (2S,3R)-2,3,4-trihydroxybutanal4 = (2R,3S)-2,3,4-trihydroxybutanal

R

R

y y L threose

C

H OH

D-ribose

O H

D-arabinose

H OH

L-ribose L-arabinose D-xylose D-lyxoseL-xylose L-lyxose

H OH

CH2OH

C

HHO

OH

HHO

HHO

CH2OH

C

HO H

O H

H OH

H OH

CH2OH

C

OHH

OH

HHO

HHO

CH2OH

C

H OH

O H

HO H

H OH

CH2OH

C

HHO

OH

OHH

HHO

CH2OH

C

HO H

O H

HO H

H OH

CH2OH

C

OHH

OH

OHH

HHO

CH2OH

R

R

R

C

H OH

O H

H OH

H OH

C

HHO

OH

HHO

HHO

C

HO H

O H

H OH

H OH

C

OHH

OH

HHO

HHO

C

H OH

O H

HO H

H OH

C

HHO

OH

OHH

HHO

C

H OH

O H

H OH

HO H

C

HHO

OH

HHO

OHH

R

R

R

32

D-allose D-altroseL-allose L-altrose D-glucose D-gluoseL-glucose L-gluose

OHH

CH2OH

HO H

CH2OH

OHH

CH2OH

HO H

CH2OH

OHH

CH2OH

HHO

HO H

CH2OH

HO H

OHH

CH2OH

HO H

CH2OH

C

HO H

D-mannose

O H

D-galactose

HO H

L-mannose L-galactose D-idose D-taloseL-idose L-talose

H OH

OHH

CH2OH

C

OHH

OH

OHH

HHO

HO H

CH2OH

C

H OH

O H

HO H

HO H

OHH

CH2OH

C

HHO

OH

OHH

OHH

HO H

CH2OH

C

HO H

O H

H OH

HO H

OHH

CH2OH

C

OHH

OH

HHO

OHH

HO H

CH2OH

C

HO H

O H

HO H

HO H

OHH

CH2OH

C

OHH

OH

OHH

OHH

HO H

CH2OH

R

4/3/2017

17

Famous Drugs

Psychoactive drugs - chemical substances that affect the function of the central nervous system, altering perception, mood or consciousness: ethanol (depressant: wine beer hard liquor chough medicines etc ) nicotine (stimulant: cigarettes cigars

H3C

H2C

OHN

N

O

H3C

CH3

NH

wine beer, hard liquor, chough medicines, etc.), nicotine (stimulant: cigarettes, cigars, pipes, patches, drops, etc.) and caffeine (stimulant, estimated used by 90% of the population: coffee, tea, chocolate, etc.) are the most widely consumed psychoactive drugs used worldwide and are also considered recreational drugs since they are used for other than medicinal purposes

33

3

ethanol

nicotinecaffeine

N NO

CH3

N

CH3

Other recreational drugs: hallucinogens (LSD), opiates (morphine, heroin) and amphetamines (phenethylamine has been used to treat ADHD, narcolepsy and obesity, methamphetamines), also use can be spiritual or religious (mescaline from peyote used by indigenous peoples for about 6,000 years, cannabis (THC = tetrahydrocanabinol) used for spiritual purposes for about 4,000 years)

O

Lysergic acid diethylamide (LSD)

morphine(and heroine)

HO

RR2

phenethylamines(huge variety) NH2O

mescaline

One Hundred Years of Solitude (1967) 7 generations of Buendia family in Columbia

features mescaline and ghostsGabriel García Márquez

Epinephrine, also known as adrenalin

HNHO

OH

N

HN

O

CH3

N

H

HO

H

HO

NCH3

H

HN

RN

R

RR

R3

R4

R5

R6

O

O

O O

Methylphenidate(ritalin)* = chiral center

*

*

**

**

*

* *

*

34

HN

CH3

CH3

methamphetamine (racemic, free base) levomethamphetamine (weaker) and dextromethamphetamine (stronger)

CH3

CH3HO

HOtetrahydrocanabinol

THC

O

OH

H

H

HN

*

*

* *

*

* *

4/3/2017

18

H

H

OH

O O

HO

O

C38H58O14

Mol. Wt.: 738.86

OO

therapeutic amount = 2 x 10-9g / mL = 3 x 10-12 moles / mL = 8 x 10-5g / 40L

Therapeutic Index = toxic dose (50% of subjects) / effective dose (50% of subjects), a safe drug has a high number and a dangerous drug has a low number. Or, some define it as the safe amount of drug in the blood.

Digoxin cardiac glycoside from foxglove plant: 0.8 to 2.0 ng/mL. Mainly used for atrial fibrillation, atrial flutter, and heart failure, taken by mouth or by injection into a vein.[

complicated

H

O

HO

O

O

HO

O

O

HO

HO O

lithium: 0.8 to 1.2 meq/L (toxic over 1.5 meq/L)

OH OOLiLi

lithium citrate - used to treat bipolar depressionC6H5O7Li3

pmedicine

(8x10-5g / 40L)(1 mol/800g)(1023 molecules/mol) = 1x1017 moleculesmoleculescell =

100,000,000,000,000 cells1x103 molecules

cell

35

OO

O OLi

therapeutic amount = 1 x 10-3meq Li / L = 0.33 x 10-3 mmoles salt / L = 2 g salt / 40L

Mol. Wt.: 201

older method

LD50= lethal dose, 50% of subjects

ED50 effective dose, 50% of subjects

simplemedicine

(2g / 40L)(1 mol/200g)(6x1023 molecules/mol)(3 Li/molec.) = 18x1021 moleculesLi+cell =

100,000,000,000,000 cells ( 1014 cells) 2x107 Li+

cell

Water distribution in people is estimated to be 48 ±6% for females and 58 ±8% water for males (averages). Water constitutes as much as 73% of the body weight of a newborn infant.  Body water and salt is regulated by hormones (anti‐diuretic hormone = ADH = vasopressin), aldosterone and atrila natriuretic peptide.

Body water can be broken down into the following compartments: 

Intracellular fluid (about 2/3 of body water). Per Guyton: in a body containing 40 litersIntracellular fluid (about 2/3 of body water).  Per Guyton:  in a body containing 40 liters of fluid, about 25 liters is intracellular, which amounts to 62.5% (5/8), close to the 2/3 rule of thumb  ( 6 gallons)

Extracellular fluid (1/3 of body water). Per Guyton: in a body containing 40 liters of fluid, about 15 liters is extracellular, which amounts to 37.5%, close to the 1/3 rule of thumb.   ( 4 gallons, donate a pint in blood donation  1/32  3%)

Plasma (1/5 of extracellular fluid). Per Guyton: of the 15 liters of extracellular fluid, 

36

plasma volume averages 3 liters.  Interstitial fluid (4/5 of extracellular fluid), transcellular fluid (a.k.a. "third space," normally ignored in calculations), inside organs, gastrointestinal, cerebrospinal, peritoneal and ocular fluids.

Estimates are for about 6 quarts of blood flow per minute, 83 gallons per hour and 2,000 gallons per day.  Blood circulates through the body in about 1 minute.Video of blood flow:  http://www.brainstuffshow.com/blog/how‐fast‐does‐blood‐flow‐throughout‐the‐human‐body/

4/3/2017

19

Pain relivers = analgesia, relief from pain. (many possibilities)

HOH

OHO

O

O

Aspirin (MW = 180)

O

ibuprofen (MW = 206)(Advil, Motrin)

OHN

H

37

O

HO

O

acetaminophen (MW = 151)(Tylenol)

O

naproxen (MW = 230)(Aleve, Naprosyn)

HO

N

O

HThe good: It is used to treat pain and fever and appears to act centrally in the brain, rather than peripherally in nerve endings. It is often sold in combination with other drugs (cold medications and opioid pain medications for cancer or after surgery). Its mechanism of action is not well understood. It is thought to inhibit COX enzymes (cyclooxygenase 1 (has isoleucine at position 523 in active site) and cyclooxygenase 2 (has smaller Val523 there), 65% homologous and very similar active i ) hi h b li f hid i id bl

Tylenol or paracetamol or acetaminophen or APAP - most commonly used medication for pain and fever

T l l (MW 151)

The bad: Use at high dosages can cause liver failure. It is the most common cause of liver failure in the US and UK. Damage to the liver, or hepatotoxicity, results not from acetaminophen itself, but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). which

O

N

O

H

N-acetyl-p-benzoquinoneimine (NAPQI)

Toxic metabolite

sites), which prevents metabolism of arachidonic acid to 'unstable' protaglandin H2, which is converted to pro-inflamatory compounds. It also may inhibit the uptake of anandamide, increasing concentrations of endogenous cannabinoids, modulating pain pathways and lowering body temperature. It may also block synthesis of nitric oxide. The half life in adults is about 3 hours, but is longer in infants, so the dose gets progressively lower the younger the patient.

Tylenol (MW = 151)

38

depletes the liver's natural antioxidant glutathione and directly damages cells in the liver, leading to liver failure.

(NAPQI)

H3N CO2

H

valine

H3N CO2

H

isoleucineTypical dose = 2 tablets = 625 mg = 0.625 g = 0.0041 mole = 2.5 x 1021 molecules x 5 times/day = 1022 molec/day

# molecules/cell = 1022 molec/1014 cells = 100,000,000 molecs/cell

COX 1COX 2

4/3/2017

20

HO

N

O

H

Toxic metabolite

The good: It is used to treat pain and fever and appears to act centrally in the brain, rather than peripherally in nerve endings. It is often sold in combination with other drugs (cold medications and opioid pain medications for cancer or after surgery). Its mechanism of action is not well understood. It is thought to inhibit COX enzymes (cyclooxygenase 1 (has isoleucine at position 523 in active site) and cyclooxygenase 2 (has smaller Val523 there), 65% homologous and very similar active sites), which prevents metabolism of arachidonic acid to 'unstable' protaglandin H2, which is converted to pro-inflamatory compounds. It also may inhibit the uptake of anandamide, increasing concentrations of

Tylenol or paracetamol or acetaminophen or APAP - most commonly used medication for pain and fever

Tylenol (MW = 151)

The bad: Use at high dosages can cause liver failure. It is the most common cause of liver failure in the US and UK. Damage to the liver, or hepatotoxicity, results not from acetaminophen itself, but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). which depletes the liver's natural antioxidant glutathione and directly damages cells in the liver, leading to liver failure.

O

N

O

H

N-acetyl-p-benzoquinoneimine (NAPQI)

also may inhibit the uptake of anandamide, increasing concentrations of endogenous cannabinoids, modulating pain pathways and lowering body temperature. It may also block synthesis of nitric oxide. The half life in adults is about 3 hours, but is longer in infants, so the dose gets progressively lower the younger the patient.

COX 1COX 2

39

NH

C

H

valine-523 isoleucine-523

Typical dose = 2 tablets = 625 mg = 0.625 g = 0.0041 mole = 2.5 x 1021 molecules x 5 times/day = 1022 molec/day

# molecules/cell = 1022 molec/1014 cells = 100,000,000 molecs/cell

COX 1COX 2

protein

O

HN

protein NH

C

H

protein

O

HN

protein

12

34

56

7

8

9

10

11

12

1314

15

16

1718

linoleic acid (LA)18:2n-6

O

HO1

23

45

6

7

8

9

10

11

12

1314

15

16

1718

-linolenic acid (LA)18:3n-6

O

HO

dihomo--linolenic acid (LA)20:3n-6

HO

O

12

34

56

7

8

910

1112

1314

15

16

1718

1920

enzymereactions

(add a double bond)

We need this from our diet.

Our bodies

enzymereactions

(add 2 carbons)

Linoleic acid is an essential, polyunsaturated fatty acid used in the biosynthesis of arachidonic acid (AA) and thus some prostaglandins, leukotrienes (LTA, LTB, LTC), and thromboxane (TXA). It is found in the lipids of cell membranes. It is abundant in many nuts, fatty seeds and their derived vegetable oils. It comprises over half (by weight) of poppy seed, safflower, sunflower, corn, and soybean oils. It must be consumed for proper health. A diet only deficient in linoleate (the salt

HO

O

12

34

56

7

8

910

1112

1314

15

16

1718

1920

arachidonic acid (AA)20:4n-6

NH

O

12

34

56

7

8

910

1112

1314

15

16

1718

1920

HO

enzymereactions

Our bodiescan do this as part of our fatty acid metabolism.

enzymereactions

(add a double bond)

40

o y de c e t o eate (t e sa tform of the acid) causes skin scaling, hair loss, and poor wound healing in rats

HO

O

12

34

56

7

8

9

10

111213

1415

1617

1819

20

prostaglandin H2(blood clotting, immune response) O

O

anandamide - fatty acid neurotransmitter and found as the natural receptor for 9-THC compounds in

cannabis (tetrahydrocannabinol in marijuana).

OH

enzymereactions

R

R

8

9

10

11

12

O

OO

O

89

10

1112R

R

O

O

89

10

1112R

R

prostaglandin H2

oxygenor

P-450

4/3/2017

21

O

OH

OH

O

OHHO

O

O

OHHO

O

OHO

O

PGJ2

https://en.wikipedia.org/wiki/Prostaglandin_H2 (prostaglandins are 20 carbon compounds that do many things, stop bleeding, part of immune response, cause inflammation, temperature control, etc.)

O

OH

O

O

OH

OHO

HO

OHHO

HO

O

OHO

O

HO

O

OH

OHHO

HO

ProstacyclinSynthase

PGD26-keto-PGF12

PGI2

Prostaglandin H2

PGF2

PGE2

PGD synthase

PGE synthase

PGE 9-ketoreductase

41

O

OH OH

O

OH

OH

O

HO

O

OH

OH

O

O

O

O

OH

OH

OHHO

PGA2PGB2TXA2

ThromboxaneSynthase

How does acetaminophen cause liver damage? We need to look at some related biomolecules. You are not responsible for these mechanisms.

FAD / FADH2 - Flavin adenine dinucleotide (oxidation - reduction) - used to deliver hydride to C=C or take hydride from CH-CH (fatty acid metabolism, TCA cycle and electron transport chain in mitochondria)

FAD - flavin dinucleotide (a hydride acceptor)

N

N

H

BH

Hydride transfer

simplified structures for FAD and FADH2

CC

R

R

R

R

hydride transfer N

BH

C

R

R C

R

R

HHO

O O

O P

O

O

O P

O

O

OO

N

NNH2

N

N

N

H

FAD - flavin dinucleotide (a hydride acceptor)

FADH2 - flavin dinucleotide (a hydride donor)

reduces FAD to FADH2.

hydride transferfrom FADH2. reduces C=C, makes FAD

N

N

B

C

H

R C

R

R

HR

B

CC

R

R

R

R

O O

42

N

N

NH

N

O

O

OH

HOOH

O O

HOOH

N

NN

actual structure

atypical nitrogen (electron poor)

N

N

NH

N

O

O

R

resonanceN

N

NH

N

O

O

R

only 6 e-

4/3/2017

22

Aldopentoses - 5 carbon aldehyde carbohydrates, naturally occuring carbohydrates tend to be D, 3 chiral centers leads to 23 = 8 possible stereoisomers (naturally occurring aminoacids tend to be L with "S" chirality)

HO O

OH

OH

OH

D-arabinose

HHO

O H

HO O

OH

OH

OH

D-lyxose

HHO

O H

HO O

OH

OH

OH

D-ribose

OHH

O H

HO O

OH

OH

OH

D-xylose

OHH

O H

*** * * * * * * * * *

SS R R

H OH

H OH

H2COH

HO H

H OH

H2COH

H OH

H OH

H2COH

HO OH

H OH

H2COH

R

R

S

R R R

R S

enantiomer enantiomer enantiomer enantiomer

Ketopentoses - 5 carbon ketone carbohydrates, naturally occuring carbohydrates tend to be D, 2 chiral centers leads to 4 possible stereoisomers (naturally occurring aminoacids tend to be L with "S" chirality)

HO OH

OH

HO OH

OH

** * *N

N

NH2

O

5-phosphate

43

OOH

D-ribulose

O

H OH

H OH

H2C

OH

OH

OOH

D-xylulose

O

HO H

H OH

H2C

OH

OH

R

R

S

R

enantiomer enantiomer

NN

O

OHOH

HH

HH

O

P OO

O

adenosine monophosphate (AMP)

adenosine

ribose

1

23

4

5can

rotate here

Keto / Enol tautomerization is a common transformation, happens twice in glycolysis.

BH

OOH

OH

HOHO

HO

* = chiral center

**

* * *

25 = 32 possible stereoisomers for cyclic aldohexoses

RRRR

SSSS

SRRR

RSSS

RSRR

SRSS

RRSR

SSRS

RRRS

SSSR

SSRR

RRSS

RSSR

SRRS

SRSR

RSRS

D-glucoseepimeric center ( / )

OOH

OH

HO**

* * *

OOHHO

HO

HO

**

* * *

D-glucose D-galactoseD-mannose

OHOH

OH

O

H

H OH

HO

OH

OH

OB

BHO

H

HO

OH

OH

O OH

H

B

O

H

HO

OH

OH

O O

H

D-glucose-6-phosphate24 = 16 possible stereoisomers

endiol D-fructose-6-phosphate

BHO OO

2 32 possible stereoisomers for cyclic aldohexoses

****

O3P O3P O3P

-2 -2 -2

Henzyme enzyme

D-mannose D-galactose

44

O

H

H OH

O

B

BHO

H

O

OH

H

B

O

H

O

O

H

D-glyceraldehyde-3-phosphate endiol dihydroxyacetonephosphate

PO

O

PO

O

PO

OH

Most of life makes D carbohydrates, though some bacteria can make both kinds (self defense).

enzymeenzyme

4/3/2017

23

NAD+ and NADP+ - nicotinamide adenine dinucleotide (hydride acceptor)

N

NN

N

NH2

O

OHOH

HH

HH

P

O

O

OP

O

OH2C

O

CH2O

=

O

OH HO

N

CONH2

N

R

NADP+ has a phosphate here.

actual structure

simplified structure

1

2

3

4

5

6

Why is C4 electrophilic? similar role in

organic chem: Jones, PCC, Swern oxidation

phosphate here.

NADH and NADHP - nicotinamide adenine dinucleotide (hydride donor)

N

NN

N

NH2

O

OHOH

HH

HH

P

O

O

OP

O

OH2C

O

CH2O

=

O

OH HO

N

CONH2

N

R

NADPH has a phosphate here

HH

H4aH4b

Why is H4 nucleophilic?

similar role in organic chem: NaBH4, LiAlH4

45

phosphate here.

O

N

N

H

HBH

N

N

Transfers 2e-s and 2H, possibly as hydride and a proton or in free radical transfers.

NAD+

NRH

H

FAD(simplified)

oxidizedFADH2

(simplified)reduced

NR

NADH

H

B BH

N

N

NRH

H

FAD(simplified)

oxidized

NADH

reverse

OO

O

O

R

O

O

O

RO

R

triglyceride - fatty acid chains are often 16-18 carbons long

enzyme ester

hydrolysis

O

O

R

fatty acid chain

O P

O

O

O

O P

O

O

O P

O

OATP

O

O

R

P

O

O

O

mixed anhydride

ENZ-1S

S

O

R

ENZ-1

acyl-CoA high energy thioester

H H

H H

N

H

BH

N

N

FAD

fatty acid catabolism - most reactions in biochemistry are under enzyme controlH

O H

B H

H

HB H

B

B

B

B

carbons long

N

H

NAD+

N RH

N R

NADH

H

FADH2

S

O

R

ENZ-1

H

H

H

O HB H

S

O

R

ENZ-1

H H

O H

H

S

O

R

ENZ-1

H H

O

ENZ-2S

B H

S

O

ENZ-1

S

O

R

ENZ-2

acyl CoA (2 carbons shorter,

cycle repeats),-unsaturated thioester

-hydroxythioester-ketothioesterB

H

B H

CoA S

B

B

B

B

B

46

N RH

acetyl CoA - involved in many biochemical

cycles in the body

O P

O

O

O P

O

O

O

O

HOOH

N

N

NN

NH2

OH

O

NH

O

NH

HS

Thiol esters form here.

O

S CoAAcetyl Co-A =

All of this is "Co-A"

actual structure

simplified structure

Co-AHS

This is an acetyl group

CoA S

H

S

O

CoAENZ-1 S

H

repeat

modify DNA, histones: effects gene expression, glycolysis, TCA cycle, fat metabolism, many things.

4/3/2017

24

O

O

R

O

O

O

RO

R

triglyceride - triester of glycerol

saturated fatty acid chain (no C=C bonds)fatty acid structures

O

HO 1

34

56

78

910

1112

O

HO 1 34

56

78

910

1112

1314

O

HO 1 3 5 7 9 11 13 15

Myristic acid, C14 tetradecanoic acid

Palmitic acid, C16

Lauric acid, C12dodecanoic acid

1

234

5678

910

1112

HO 34

56

78

910

1112

1314

1516

O

HO 1 34

56

78

910

1112

1314

1516

1718

Palmitic acid, C16hexadecanoic acid

Stearic acid, C18octadecanoic acid

O

HO 1 34

56

78

9 1011

Linoleic acid, 18:2n-618:2 cis,cis-9,12

cis-9-Octadecenoic acidOleic acid, 18:1 cis-912

1314

1516

1718

O

HO 1 34

56

78

9 1011

12 1314

1516

1718

12

34

56

78

9

1

23

45

678

9

= D = double bond

O

O

R

O

O

O

R

P

O

diglyceride - phosphatidyl choline

O

HO N

CH3

CH3

CH3

47

HO

O

12

34

56

7

8

910

1112

1314

15

16

1718

1920

arachidonic acid (AA)20:4n-6

12

34

56

7

8

9

10

11

12

1314

15

16

1718

linoleic acid (LA)18:2n-6

O

HO

oleic acid (LA)18:1n-9

What came first in life? amino acids proteins, nuclotide bases RNA DNA,fats & lipids membranes,carbohydrates structure, energy,...or some combination of all of these

9 10

11 12

13 14

15 16

17 18

87

65

43

21O

HO

Fe

N

N

N

N

Example of cytochrom P-450 oxidative enzymes, common in the liver, protoporphyrin, the iron sits in the middle of a complicated heme molecule. There are over 21,000 distinct P-450 enzymes known.

N

N

N

N

Fesimplified structure,binds to enzyme through a sulfur enzyme, cysteine

+3

Fe+3

+3

The proteins are complicated

HO2C

CO2H

Enz

SH

B

S

Enz

ready for oxidation reactions shown below(symbolic cytochrom P-450 enzymess)

Fe

All extraneous parts are left out to show only the iron atom in an oxidized state.

anchored to enzyme, hemoglobin uses

imidazole of histidine

48

The proteins are complicated and can hold iron‐heme complexes.

4/3/2017

25

1.�Ferric iron ion abstracts an electron from flavin mononucleotide (FADH2), an enzyme co-factor, and is reduced from +3 to +2.2.�Iron gives up an electron to make a bond with oxygen. (+2 to +3). Possible radical reactions with oxygen.3.�Oxygen atom abstracts an electron from flavin mononucleotide (FADH FAD), an enzyme co-factor.4.�FAD gets reduced by NADH (hydride donor) and picks up a proton to reform FADH25.�The basic oxygen anion picks up a proton (or two?) from an acidic enzyme site.6.�A weak O-O bond breaks homolytically (hydroxyl radical) or heterolytically, and releases water. 7.�An electron is supplied from iron to stabilize the oxidized oxygen atom. +3 to +4, which is now ready to oxidize bio-molecules.

Steps shown below in cytochrome P-450 oxidations (and next slide)

B H

NAD+ NADH

1e-

FAD

O

O

Fe+3 FADH2

Fe+2

Fe+3

OO

FADH

Fe

OO

+3

+H+

12 3

45

1e-

8, 9, 10(see next)

OO

superoxide

possible

49

Possible leakage of hydroxyl radicals (extremely dangerous in the body), but also part of body's immune defense in all out warfare, collateral damage possible.

OH

Fe

OO

+3

HB H

Fe

OO

+3

HH

Fe+4

O

678, 9, 10

(see next)Fe+3

homolytic

heterolyticH2O

Every step represents a protein target for a medicine. Side effects occur when other biochemical reactions are also affected.

reactiveperoxide

8.�The free radical-like oxygen atom converts a C-H bond to an C-OH bond via free radical chemistry9.�The free radical-like oxygen atom converts a C=C bond to an epoxide via free radical chemistry10. The free radical-like oxygen atom converts a N or S lone pair to an N-O or S-O bond. The iron is reduced back at Fe+3 to begin the process all over again.

C

COH

Fe +4

O CH

Fe +4

OH

Fe +3

sp3 C-H bonds alcohols8

hydrophobicbecomes....

hydrophilic

Nature's magic tricks.

The free radical-like oxygen atom abstracts a hydrogenatom from a C-H bond in the enzyme cavity, forming an O-H bond and a carbon free radical.

The carbon free radical abstracts hydroxyl (OH) from iron, making an C-OH bond where a C-H bond had been. The iron is reduced back at Fe+3 to begin the process all over again.

9

The free radical-like oxygen atom adds to a C=C bond (alkene or aromatic) in the enzyme cavity,

Fe +4

O

Fe +4

O

The carbon free radical abstracts the oxygen atom from the iron, making an epoxide ring. The iron is reduced back at Fe+3 to begin the process all over

Fe +3

CC

O

R

RRR

epoxides

C C

R

R

R

R

CR

R

C

R

R

B H

O

H

HB

CC

R

R

HO

OH

RR

Diols are much more water soluble, can be eliminated from the body.

alkenes or aromatics

hydrophilic

hydrophobicbecomes....

50

( ) y yforming a O-C bond and a carbon free radical.

p g g pagain. Reactive epoxides can be opened up to diols (more water soluble).

R

SR

sulfursubstrate

(1e-)

R

SR

sulfursubstrate

S

RR

O

sulfoxides, further oxidation is possible, all the way to sulfate, SO4

-2

N

RR/H

O

N-oxides, further oxidation is possible, all the way to nitrate, NO3

-1

R

Fe +4

O

Fe +4

OFe +3

10

(nitrogen too)

4/3/2017

26

Toxicity of acetaminophen

HO

N

O

H

acetaminophen

Fe +4

O

HO

N

O

H

Fe +4

O

HO

N

O

Fe +3

O

N-hydroxylation by cytochrome P-450 (too much acetaminophen uses up all the capacity of the enzyme to oxidize target molecules)

( 20%)

OH

H

H

HO

O

N

O

O

H

HB

gluconidationconjugation

( 50%)

sulfonationconjugation

( 30%)

O

N

O

O

OH

OH

HO

HOO

N

O

H

SO O

O

H

B HToo much acetaminophen uses up the P-4450 oxidizing power of the liver. Other compounds that need oxidation are not oxidized and can build up to toxic levels.

makes thesemore water soluble

51

O

N

O

N-acetyl-p-benzoquinoneimine (NAPQI)

Toxic metabolite(see next slide)

Conjugation joins xenomolecules with biomolecules, usually helps to eliminate them from the body in the urine (kidneys) or feces (intestines).

OO O

Furanocoumarins are found in citrus fruits and can cause similar problems when taking certain medicines.

Psoralen is a mutagen found in grapefruit, and is used for this purpose in molecular biology research. Psoralen intercalates into the DNA and, on exposure to ultraviolet (UVA) radiation and can form monoadducts and covalent interstrand cross-links (ICL) with thymines preferentially at 5'-TpA sites in the genome, inducing apoptosis (cell death).

Tylenol 100,000,000 molecs/cell (that doesn't mean they all getting into the cell)

O2C

O

N

HH3N

HS

O

N

H O

O

glutathione (5mM in cells)(about 300,000,000 / cell)

Vol 10-13 L

Glutathione is an important reducing agent in body (can provide electrons from sulfur).

RS

H

Glutathione also protects against toxicity by conjugating with metabolites, making them water soluble and excreting them. The bodies store of glutathione is used up

glutamic acid(backwards) cysteine glycine

glutathione(tripeptide)

O

N

O

RS

H

glutathione conjugation with NAPQI

BBH

HO

N

O

H

SR

glutathione is used up reacting with NAPQI. The sulfur atom can also quench free radicals.

Other important anti-oxidants found in the body: glutathione, vitamin C and vitamin E. All protect against free radical damage in the body Food can be medicine too and food can be toxic!

(backwards)

glutathione

52

damage in the body. Food can be medicine too, and food can be toxic!

O O

OHHO

HO

HO

vitamin C (ascorbic acid)electron rich anti-oxidant

water soluble (blood and cytosol)

O

HO

vitamin E (-tocopherol)electron rich anti-oxidant

fat soluble (in membranes)there are several variations

4/3/2017

27

HO

O

O

O

Osaturated fatty acid chain

HO

OH

O

O

O

Osaturated fatty acid chain

The damage

Possible membrane damage from free radicals and possible protection from vitamins E and C.

dangerous uncontained free radical

unsaturated cis fatty acid chains in cell membrane

O O

HO

O O

Osaturated fatty acid chain

OH

OO

Osaturated fatty acid chain

Free radicals reacting with unsaturated fatty acid pi bonds can possibly cross link fatty acid chains, making cell membranes more rigid and less functional over time, leading to cell death.

OH

diglycerides in cell membranes

53

unsaturated cis fatty acid chains in cell membrane

O O

OH

continueddamage

The protection

O

O

R

H

vitamin E located in cell membranes

O

O

R

H

O

O

R

H

OHO H

hydroxide is

resonance and inductive effects stabilize radical so it does not do damage

HO

resonance

hydroxyl free radical = danger

HOin cell membranes quenches radicals

OO

O

H

H R

O

O

R

H

O

O

O

O

H

H R

O

O

O

O

H

H

O

O

O

O

H

RR

Bprotects a second time

O

H Bhydroxide isneutralized by body's buffer system

vitamin C reduces vitamin E back to normal and ultimately washes out of the body, vitamin C is 4 steps away from glucose.

B

HO

resonance

54

O O

OHHO

HO

HO

vitamin C water soluble

(blood and cytosol)O

HO vitamin E (-tocopherol)electron rich anti-oxidantfat soluble (membranes)

vitamin E is recharged and still in cell membrane

OO

O R

oxidized vitamin C form washes out of the body

4/3/2017

28

O

O

O

HO

H

H

H

OH

O

O

HO

H

H

HOH

OHOH

H

O

O

HO

H

H

HOH

OH

OH

enzyme x enzyme y

1. hydration2. oxidation (NAD+)

esterification

O

O

O

O

H

H

O

O

OH

H

tautomers

OHOH

OHOH

OHaldohexoses,

glucose in some animalsmannose and galactose in plants enzyme zoxidation

(NAD+)We lost functionality of this enzyme.

Could also formhemiacetal first and then oxidize to ester.

55

OH

vitamin C

OOH

OHOH

Dogs and cats can make their own vit. C, but humans cannot. We lost the oxidizing enzyme of the last step. Some speculate that because H2O2 was also produced maybe there was some advantage in not making that. Another theory is that because vit. C regulates a stress related transcription factor that regulates 100s of stress related enzymes, we can better control the amount of vit. C by using our dietary intake. No one knows exactly why we lost this ability.

Na+ion channels

cell membrane (lipid bilayer)

HO

OH

OH

mitochondria

golgi apparatusprocesses proteins

endocellularprotein

cholesterol - helps stabilize cell membrane and source of all other body steroids.

= diglycerides, helps compartmentalize aqueous regions in the body, cell membranes, mitochondria, vacules, nucleus, etc.

exocytosis - cell transports proteins to outside endocytosis - cell transports proteins to insidemembrane proteins

Ca+2

G7 coupled protein complex, 1/3 of all medicines act on G7

proteins.

exocellularprotein

K+

nucleus

chromosomeschromatin

ribosomesendoplasmic reticulum

rough - protein synthesissmooth - lipid synthesis

lysosome

ribosomes

NH3

O2C

OH

OH

HO

HO

DNA

RNAtransscription

translationproteins

b h d t

histones

Ca+2

Ca+2

Ca+2

Ca+2ribosomes

56

Ca 2ion channels

cell membrane

Kmitochondria vacule

Biomolecules: proteins (aminoacids), carbohydrates (sugars), lipids (cholesterol) and fats (diglycerids, triglycerids), DNA and RNA, vitamins, co-factors, minerals, combinations of all of the above, etc.

carbohydratesfats, lipids, other biochemicals

ion channels

4/3/2017

29

enzymeactivesite

allostericsite

substrate

allostericactivator

binding at allosteric site

turns on enzyme

enzymeactivesite

allostericsite

allostericactivator

substrate binds t t l ti it

Aenzymecatalyst

enzymecatalyst

allostericactivator

Can be the key that turns on the enzyme engine. Can amplify

100s to 1000s of cycles.

alloster.

alloster.

signalamplification of signal

at catalytic site

allostericactivator

enzymeactive

site

allostericsite

product

B

B

allostericactivator

enzymeactive

site

allostericsite

reactsagain

enzymecatalyst

enzymecatalyst

enzymeactivesite

allostericsite

substrate

A enzymecatalystsubstrate

reacts

productreleases

alloster.

alloster.alloster.

Every step is a potential attack site for a medicine. Usually, earlier is better.

57

A B C Dreaction 1enzyme a

reaction 2enzyme b

reaction 3enzyme c

1A 100 B(x 100) (x 100) (x 100)

10,000 C 1,000,000 D

possible amplification of signal

possible feedback inhibition

Problem - The terms "hydrophilic" and "hydrophobic" are frequently used to describe structures that mix well or poorly with water, respectively. Biological molecules are often classified in a similar vein as water soluble (hydrophilic) or fat soluble hydrophobic). The following list of well known biomolecules are often classified as fat soluble or water soluble. Examine each structure and place it in one of these two categories. Explain you reasoning.

N H2NO H

R

OH

vitamin A

N

OH

OP

O

O

O

H

vitamin B6(pyridoxine)

a

c

O

O

HO

b

HO

d

HO

changes with its biochemistry, serves many roles in body

Ar ArAr

58

HO

OH

OH

vitamin C(ascorbic acid)

O

vitamin E (-tocopherol)

4/3/2017

30

Problem - Bile salts are released from your gall bladder when hydrophobic fats are eaten to allow your body to solubilize the fats, so that they can be absorbed and transported in the aqueous blood. The major bile salt glycolate, shown below, is synthesized from cholesterol. Explain the features of glycolate that makes it a good compromise structure that can mix with both the fat and aqueous blood. Use the 'rough' 3D drawings below to help your reasoning, or better yet, build models to see the structures for yourself (though it's a lot of work).

HO

H

H H

NH

HO

H

H Hsynthesized in many,

many steps in the body

HOH

OHO

O

Ocholesterol

glycolate(bil lt)1. source for steroids and bile acids syntheses in the body H (bile salt)1. source for steroids and bile acids syntheses in the body

2. important constituent of cell membranes2. transported in blood to delivery sites via VLDL LDL HDL

VLDL = very low density lipoprotein, has high cholesterol concentrationLDL = low density lipoprotein, has medium cholesterol concentrationHDL = high density lipoprotein, has low cholesterol contcentration

All polar groups are on the same face. Which side faces water and which side faces fat molecules? (See structures below.)

HO OH

OH

OH

CO2

representation of cholesterol as a long flat shape

representation of bile acid (glycolate) as a long bent shape havingtwo different faces, one polar and one nonpolar

Glycolate has a nonpolar, hydrophobic face that can cover the inside of a fat ball and a hydorphilic face that can point

OH

OH

HO

HOblood

H2O

H2OH O

blood

H2O blood

59

OH

OH

OH

CO2

y p poutward toward the aqueous blood, which allows fats to be transported throughout the body to reach fat storage cells and other essential locations. There is a whole family of bile acids that are produced from cholesterol. The body produces about 1 gram of cholesterol each day and about half of that is converted into bile acids that are released into the intestine to help absorb fats. About 12-18 grams of bile acids are released each day and most of that is reabsorbed and recirculated (95%). The rest is lost in the feces. The body's store of bile acids is about 4-6 grams.

OH

OH

CO2

HO

O2C

HO

HO

HO

O2C

nonpolar fats and cholesterol

inside

2O

blood

H2O

blood

H2O

bloodH2Oblood

H2O

blood

H2O

blood

H2O

H2O

= water molecule

Water molecules rigidly order themselves around a nonpolar molecule. This is an entropy expense (S is lower) and increases free energy, G (less favorable).

G = H - TS

nonpolar

Nonpolar molecules associate together, separate from water. The water molecules are less structured, more disordered this way. This is an entropy gain (S is higher) and free energy, G is more negative (favorable). Nonpolar molecules are said to be hydrophobic The

Weak dispersion forces.

hydrophobic effect

nonpolar

nonpolar

nonpolar

60

said to be hydrophobic. Thenonpolar compounds float or sink based on relative density.

compound density dipole momentwater 1.0 g/cm3 1.8 Doctane 0.8 g/cm3 0 Dcarbon tetrachloride 1.6 g/cm3 0 D

4/3/2017

31

Biopharmaceutics Classification System - classifies drugs according to their solubility and permeabilty or absorption properties. This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection. All those factors are highly important because 85% of the most sold drugs in the United States and Europe are orally administered.

According to the Biopharmaceutics Classification System, drug substances are classified as follows:

Class I - high permeability, high solubility. Compounds that are well absorbed and their absorption t i ll hi h th ti E l t l lrate is usually higher than excretion. Example: metoprolol

Class II - high permeability, low solubility. The bioavailability of these products is limited by their solubility. A correlation between the in vivo bioavailability and the in vitro solubility can be found. Examples: glibenclamide, bicalutamide, ezetimibe, phenytoin

Class III - low permeability, high solubility. The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied. Example: cimetidine

Class IV - low permeability, low solubility. These compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected Example:

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they are not well absorbed over the intestinal mucosa and a high variability is expected. Example: hydrochlorothiazide, Bifonazole

•A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.

•A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose in comparison to an intravenous reference dose.

•A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes in a volume of < 900 ml buffer solutions.

O

OHN

OHMetoprolol, (tradename Lopressor) is used to treat high blood pressure, various heart problems and migraine headaches. It may be combined with the diuretic hydrochlorothiazide. Metoprolol was first made in 1969. It is available as a generic drug. In 2013, it was the 19th most prescribed medication in the United States.

Class I - high permeability, high solubility

O OS

O O

NH

O

NH

Class II - high permeability, low solubility

Cl

NH

H H

Class III - low permeability, high solubility

Glibenclamide is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfonamide antibiotics. It was developed in 1966.

HN

N SNH

N

NH

CN

Cimetidine (Tagamet) is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mostly used in the treatment of heartburn and peptic ulcers. It was discovered in 1971 and marketed in 1976.

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Class IV - low permeability, low solubility

H H

N

N

Bifonazole is an imidazole antifungal drug. Bifonazole is marketed under the trade mark Canespor in ointment form.

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Pharmacokinetics - what the body does to the drug (the fate of the drug in the body)

Pharmacodynamics - what the drug does to the body (mechanism of drug action on the target site)

A common descriptor describing the fates of drugs inside the body is ADME

Absorption - the process of a substance entering the blood circulation.

Distribution - the dispersion or dissemination of substances throughout the fluids and tissues of the body.

Metabolization (or biotransformation, or inactivation) – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into secondary metabolites.

Excretion - the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.

The two phases of metabolism and excretion can also be grouped together under the title elimination. The study of these distinct phases involves the use and manipulation of basic chemical concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients (substances added to

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mouth stomach intestines blood liver

various tissues

kidneys

lymphatic system

urine

feces

blood brain barrier?

factors such as: the properties of the substances that act as excipients (substances added tostabilize the drug), the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug.

interstitial tissues

Pharmacokinetics

drug

target

Pharmacodynamics

interaction

brain

Naming systems

Letters and numbers are used for drugs in early research (lead compounds). Letters are specific to the research company undertaking the research and numbers are for the specific compound being studied. There may be 100s to 1000s of derivatives made.

Book examples of anti-HIV drugs.

Ro31-8959 ABT-538 MK-639 early researcho3 8959(Roche) (Abbott) (Merck)

saquinavir ritonavir indinavir

Norvir Crixivan

Fortovase 200 mg of saquinavir in a gel-filled beige-colored capsule.

Invirase 200 mg of saquinavir as the mesylate salt in a brown/green capsule

Fortovase

names in testing

Trade names

different formulations

early research

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Invirase 200 mg of saquinavir as the mesylate salt in a brown/green capsule

Generic drugs are not allowed to use the trade name used by the originator of the drug.

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N

HN

O

OH2N

OHN

OH

N

H

O

saquinavir

HN O

O

N

S

OH

HN

HN O

N

NS

ritonavir

N

N

O NH

OHOHN

OH

indinavir

N

Saquinavir is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS. Typically it is taken orally with ritonavir or lopinavir/ritonavir. It is in the protease inhibitor class and works by blocking the HIV protease. Saquinavir was first sold in 1995 As of 2015 it was not

Ritonavir is an antiretroviral medication used along with other medications to treat HIV/AIDS. The combination treatment is known as highly active antiretroviral therapy (HAART). It is taken by mouth and used to inhibit the enzyme that metabolizes other protease inhibitors. leading to higher concentrations of those other medications. It fi t i t i 1996 d t b t

Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. Unfortunately, indinavir wears off quickly after dosing, so requires very precise dosing every 8 hours to thwart HIV from forming drug resistant mutations Pills cost

H

O

NHO

H

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Scanning electron micrograph of HIV-1 budding (in green) from cultured lymphocyte. Color enhanced.

sold in 1995. As of 2015 it was not available as a generic medication and wholesale cost is about $4.50 per day ( $1500/year).

first came into use in 1996 and costs between$10 and $55 per day, depending on the dose ( $11,000/year).

drug-resistant mutations. Pills cost about $1.50/pill. Also, many drug interactions are possible.

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The development of indinavir started from renin inhibitors (for high blood pressure) previously made by Merck that showed inhibition of HIV protease enzymes. Renin (angotensinogenase) helps to regulate extracellular fluid and arterial vasoconstriction by inhibiting the conversion of angiotensinogen (from the liver) to angiotensin I, which is converted by angiotensin converting enzyme (ACE) to angiotensin II, which is the most vasoactive peptide. It narrows the blood vessels, retains sodium ions in the kidneys and acts on the CNS to stimulate thirst to retain water and reduces urine loss and causes the post pituitary gland to release vasopressin. All of this helps to regulate blood pressure in a very complicated sequence of steps and illustrates the incredibly complex network of interactions that must be considered when designing a drug. The best compound from the renin inhibitors for HIV inhibition was called L 364505. This was the starting point for indinavir.

Design of indinavir (Crixivan®) - HIV medicine (human immunodeficiency virus)

L364,505 (IC50 = 1 nM)

L364,505 was a potent inhibitor of HIV protease. However, its antiviral activity was low due to poor pharmacokinetics (vulnerable to degradative enzymes, rapid biliary clearance (gall blader) and poor oral absorption). Several smaller molecules were made in hopes to find one with similar activity.BocPhePhe

N

O

LeuPheNH2

H OH

Ph

Ph

P' = right half of moleculeP = left half of molecule

IC50 = is the amount of an inhibitor to decrease a biological process by half. It is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function.

Phe = phenylalanine and Leu = leucine amino acids

removed

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The left two "Phe" amino acids could be removed without loss of activity (from the P side) against HIV protease. It lacked any activity against renin (that's a good thing).

N

O

LeuPheNH2

H OH

Ph

Ph

O

O

(Boc)

L682,679 (IC50 = 0.6 nM) removed

next slide

The right two amino acids (Phe and Leu) could be removed and replaced with a benzyl group (compound II). A drop in activity occurred, but it did not dissappear, which meant they could keep trying to make improvements.

N

O

NH

H OH

Ph

Ph

O

O

compound II (IC50 = 111 nM)

P = left half of molecule P' = right half of molecule

N

O

N

H OH

Ph

Ph

O

O

compound III (IC50 = 21 nM)

H

It was thought that greater rigidity would help fit better in the binding pocket, so an indan derivative was made (compound III). Five fold improvement in the IC50 was observed, but III had poor oral bioavailability and poor water solubility. It was thought that introducing a polar substituent would help.

more rigid

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N

O

NH

H OH

PhO

O

L 685,434 (IC50 = 21 nM)

An "OH" was added and antiviral activity increased 70 fold, but there was still poor oral bioavailability and poor water solubility.

OH

H

greater polarity

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P = left half of molecule P' = right half of molecule A nitrogen atom was introduced to the right side (P') of the molecule to help oral bioavailability and water solubility. A molecular modeling exercise was carried out (in silico) and showed that the aromatic rings were pointing away from the active side and faced out towards the enzyme surface. It was felt that it should be possible to add substituents "para" on the aromatics which could increase water solubility, but not interfere with the active site, leading to L 689,502. The morpholine group is know to increase water solubility and was connected with a hydroxyethylene spacer.

N

O

NH

H OH

PhO

O

OH Th li ht d i ti it b t thL 689,502 (IC50 = 0.45 nM)

OH

ON

OThere was a slight drop in activity, but the antiviral activity went up as a result of improved penetration of the cell. Oral bioavailability also improved to 5%. Unfortunately, animal studies showed liver toxicity.

O

N

H H O

H

N

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It was known that the HIV active site was symmetrical, so a decision was made to combine two different features that were both effective on the different sides of the molecule. Roche already had an anti-HIV drug on the market, called saquinavire (Ro-8959/003). Merck decided to join the two together.

NH N N

HH OH

N

OH

O NH2

saquinavire (Ro-8959/003), Roche

H

H

saquinavire combined with compound III on next slide

P = left half of molecule P' = right half of moleculeL 704,486 was less active as an inhibitor of the HIV enzyme, but the decahydroisoquinoline ring provided greater water solubility and greater bioavailability (15%). Anti-viral activity was still weak. It was decided to switch in a piperizine ring. This would allow functionalization on the #4 nitrogen atom to help with binding in the S3 subsite. (It could be made hydrophobic or hydrophilic.) The additional amine would also increase water solubility and

O

NH N

H

H

O

NH

amine would also increase water solubility and bioavailability.

H

OH OH

L 704,486 (IC50 = 7.6 nM)

OON

H

S2'S2

S3

L 732,747 had improved inhibitor activity on the enzyme and better anti-viral activity in cell bases assays. It was co-crystallized with the enzyme and an X-ray structure determined. This revealed that the S2 and S2' pockets were filled and the benzoyl

piperazine ring

switched out for piperazine ring

S# = subpockets of active site

comes from L 689,502

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N

N NH

OH OH

O

O

S1S1'L 732,747 (IC50 = 0.5 nM)

S2 pockets were filled and the benzoyl group on the piperazine fitted in the lipophilic S3 binding pocket. There was still problems with crossing the cell membrane. High activity means nothing if the drug cannot get inside the cell. Many derivatives were made and it was found that replacing the phenyl ring with a piperidine ring, which was weakly basic and improved water solubility.

12

3

4

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P = left half of molecule P' = right half of molecule

N

O

NH

ON

H

S2'S2

S3

N OH OH

O

O

S1S1'L 732,747 (IC50 = 0.5 nM)

This is indinavir. It was O

ON

H

S2 S2'

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introduced in 1996 and is still used today. It has negligible inhibition of mamalian proteases, yet is active against both HIV-1 and HIV-2 proteases. It has better oral bioavailability than saquinavir and is less bound by plasma proteins (only 60%).

N

N

O

NH

OH OH

O

ON

Indinavir (MK 639, L 735,524) (IC50 = 0.56 nM)

S1

S3

S1'