CHEM-E4220 MEDICINAL CHEMISTRY

MEDICINAL CHEMISTRYCHEM-E4220

chapter #5: steroid hormones

Jan DeskaBioorganicChemistry

www.deskalab.com

16.11.2021

TODAY'S MENU

ü second lecture on steroid molecules

ü hormonal regulation influenceseverything from urine production tocancer growth

ü key ingredients in birth control

Jan DeskaBioorganicChemistry

INTENDED LEARNING OUTCOMES

ü to have a basic understanding of the functionof nuclear receptors

ü to distinguish the four basic steroid hormonefamilies

ü to explain the principle of contraceptive pills

Jan DeskaBioorganicChemistry

Hormone-control: Regulatory processes

Nuclear receptors

§ ligand-activated transcription factors

§ activate transcription of specificgenes

§ control the cellular production ofproteins and hence up- ordownregulate certain functions

Nuclear receptors

§ ligand-activated transcription factors

§ activate transcription of specificgenes

§ control the cellular production ofproteins and hence up- ordownregulate certain functions

§ consist of three domain:

ü coactivator recognition

ü DNA binding (shown right)

ü ligand binding

§ the human genom encodes for 48 nuclear receptors

nuclear receptor

hormone

coactivator RNA polymerase mRNA proteins

§ cytosolic nuclear receptors enter nucleusafter ligand binding (type 1)

Jan DeskaBioorganicChemistry

Nuclear Receptors

nuclear receptor

hormone

coactivator RNA polymerase mRNA proteins

§ cytosolic nuclear receptors enter nucleusafter ligand binding (type 1)

§ type 2, 3 and 4 nuclear receptors locatedinside the nucleus

Jan DeskaBioorganicChemistry

Nuclear Receptors

nuclear receptor

hormone

coactivator RNA polymerase mRNA proteins

§ cytosolic nuclear receptors enter nucleusafter ligand binding (type 1)

§ type 2, 3 and 4 nuclear receptors locatedinside the nucleus

§ agonistic binding triggers cascade:

• coactivator binding

• RNA polymerase association

• DNA reading and mRNA production

• mRNA translates to thecorresponding protein (via theribosome)

Jan DeskaBioorganicChemistry

Nuclear Receptors

Jan DeskaBioorganicChemistry

From Cholesterol to Steroid Hormones

adrenal glands: corticosteroids

testes: androgens

ovaries: estrogens

cholesterol

HO

H

H

cortisol

O OH

O OH

low-density

lipoprotein

Jan DeskaBioorganicChemistry

From Cholesterol to Steroid Hormones

adrenal glands: corticosteroids

H

R

OH

H

R = OH: testosterone COCH3: progesterone

testes: androgens

cholesterol

low-density

lipoprotein

HO

H

H

cortisol

O OH

O OH

Jan DeskaBioorganicChemistry

From Cholesterol to Steroid Hormones

adrenal glands: corticosteroids

H

OH

HOH

H

estradiol

H

R

OH

H

R = OH: testosterone COCH3: progesterone

testes: androgens

ovaries: estrogens

cholesterol

low-density

lipoprotein

HO

H

H

cortisol

O OH

O OH

Jan DeskaBioorganicChemistry

Confused about all those Structures?

Counting carbons tells youwhat you're dealing with...

Jan DeskaBioorganicChemistry

Confused about all those Structures?

HO

H

H

HO

H

H

cortisone

O OH

O OH

HO

H

HHO

O O OH

aldosterone

H

H

HOH

H

cholesterol

O

27 carbons

HO

H

H

O

progesterone17α-hydroxyprogesterone

OH

biosyntheticsidechaincleavage

biosyntheticsidechainoxygenation

H

OH

OH

H

H

O

OH

H

H

OH

HOH

H

estriol

H

OH

HOH

H

estradiol testosterone androdienone

biosyntheticretro-benzoin

OH

biosyntheticaromatisation

Counting carbons tells youwhat you're dealing with...

progestagens: 21 carbonsadrenal corticoids: 21 carbons + terminal OH

androgens: 19 carbonsestrogens: 18 carbons (and aromatic)

Jan DeskaBioorganicChemistry

Transport of Steroid Hormones

unlike cholesterol, lipophilic steroidhormones are not transported fromthe glands to the target organs via lipoprotein vesicles

unspecific transport via albumins

+

task-specific globulines:

§ transcortin (corticosteroids)

§ sex hormone-binding globulin(antrogens and estrogens)

testosterone bound to albumin

Jan DeskaBioorganicChemistry

Adrenal Hormones

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

HO

H

HHO

O O OH

aldosteroneH

OH

H

O OH

deoxycorticosterone

§ mineralocorticoids

mainly responsible for water and electrolyte balance

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

HO

H

HHO

O O OH

aldosteroneH

OH

H

O OH

deoxycorticosterone

synthetic mineralocorticoids used asdiuretics (= urine-producing effect), avoiding critical potassium loss

HO

H

H

spironolactone

O

O

SAc

§ mineralocorticoids

mainly responsible for water and electrolyte balance

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

§ glucocorticoids

• regulate mechanisms of the immune system (upregulation of anti-inflammatoryproteins and down-regulation of pro-inflammatory proteins)

• metabolic functions such as gluconeogenesis and glucose uptake inhibition

• cognition function (memory and attention deficit disorders)

HO

H

H

cortisone

O OH

O OH

HO

H

HHO R

O OH

R = H: corticosteron OH: cortisol (= hydrocortisone)

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

§ glucocorticoids

HO

H

H

cortisone

O OH

O OH

HO

H

HHO R

O OH

R = H: corticosterone OH: cortisol

cortisone (and adrenaline) as majorstress hormones

• elevates blood pressure and prepares for fight or flight response

• broad application as drug against allergies and inflammations, in autoimmune disorders and as immunosuppressant

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

§ glucocorticoids

HO

H

H

cortisone

O OH

O OH

HO

H

HHO R

O OH

R = H: corticosterone OH: cortisol

cortisone (and adrenaline) as majorstress hormones

• elevates blood pressure and prepares for fight or flight response

• broad application as drug against allergies and inflammations, in autoimmune disorders and as immunosuppressant

• topical application in treatment of eczema and dermatitis

• inhalative treatment of bronchial asthma and sarcoidosis (inflammatorylumps in lung)

• direct injection into joints and ligaments (in case of inflammation, injury, rheumatoid arthritis,...)

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

§ glucocorticoids

• but also: cortisone and hydrocortisone with impact on water and salt balance(glucocorticoid potency vs mineralocorticoid potency of cortisol = 1:1)

HO

H

HHO OH

O OH

cortisol

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

§ glucocorticoids

• but also: cortisone and hydrocortisone with impact on water and salt balance(glucocorticoid potency vs mineralocorticoid potency of cortisol = 1:1)

synthetic analogues with reduced mineralocorticoid effects

HO

H

HHO

O OH

prednisoloneH

OCl

H

O OH

beclometasone

OHR

HO OH

HO

F

HHO

O OH

OH

dexamethasone

HO

H

HHO OH

O OH

cortisol

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

§ glucocorticoids

• but also: cortisone and hydrocortisone with impact on water and salt balance(glucocorticoid potency vs mineralocorticoid potency of cortisol = 1:1)

synthetic analogues with reduced mineralocorticoid effects

mineralocorticoid potency:

anti-inflammatory potency:

cortisone cortisol prednisolone dexmethasone

0.8

0.8

1

1

0.6

4

<0.1

25

HO

H

HHO

O OH

prednisoloneH

OCl

H

O OH

beclometasone

OHR

HO OH

HO

F

HHO

O OH

OH

dexamethasone

HO

H

HHO OH

O OH

cortisol

Jan DeskaBioorganicChemistry

Adrenal Hormones

Adrenal glands produce two types of steroid hormones

§ glucocorticoids

• but also: cortisone and hydrocortisone with impact on water and salt balance(glucocorticoid potency vs mineralocorticoid potency of cortisol = 1:1)

synthetic analogues with reduced mineralocorticoid effects

HO

H

HHO

O OH

prednisoloneH

OCl

H

O OH

beclometasone

OHR

HO OH

HO

F

HHO

O OH

OH

dexamethasone

HO

H

HHO OH

O OH

cortisol

despite no cross-talk with androgen receptors, use of glucocorticoids isbanned as doping by WADA (except some topical applications)

Jan DeskaBioorganicChemistry

Glucocorticoids & COVID-19

Coronavirus disease 2019 (COVID-19)

§ caused by severe acute respiratory syndrome coronavirus 2

§ contagious viral infection that invades cells through binding of the viral spike proteins to the angiotensin-converting enzyme 2 (ACE2)

§ ACE2 is covering cell membranes, particularly:

• lung alveolar cells (type II)

• enterocytes of the small intestines

• endothelial cells of the blood vessels

• arterial smooth muscle cells

inflammation of upper (sinuses, throat) & lower respiratory tract (lungs)

impairment of gastrointestinal organs & kidneys

chronic damage of cardiovascular system

Jan DeskaBioorganicChemistry

Glucocorticoids & COVID-19

P. Horby et al. New Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2021436

§ dexamethasone established as treatment for severe cases of COVID-19

§ reduces inflammation, supports immune system

§ no direct anti-viral effect

§ benefitial only for hospitalized patients on oxygen therapy or on a ventilator

Jan DeskaBioorganicChemistry

Glucocorticoids & COVID-19

P. Horby et al. New Engl. J. Med. 2020, DOI: 10.1056/NEJMoa2021436

§ dexamethasone established as treatment for severe cases of COVID-19

§ reduces inflammation, supports immune system

§ no direct anti-viral effect

§ benefitial only for hospitalized patients on oxygen therapy or on a ventilator

26%23%

discharged from hospital after 28 days:63.5% vs 67.2%

Jan DeskaBioorganicChemistry

Glucocorticoids & COVID-19

https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/hospitalized-adults--therapeutic-management/

accessed: 15.11.2021

Jan DeskaBioorganicChemistry

Sex Hormones (gonadal steroids)

Jan DeskaBioorganicChemistry

Sex Hormones

All sex hormones are found both in women and men, however, hormone levels anddistribution and concentration of receptors in particular tissues differ

§ responsible for development of secondary sex characteristics during puberty

§ produced by gonadal glands (ovaries and testes)

§ fertility and reproduction

§ various other regulating functions

Jan DeskaBioorganicChemistry

Sex Hormones

All sex hormones are found both in women and men, however, hormone levels anddistribution and concentration of receptors in particular tissues differ

§ responsible for development of secondary sex characteristics during puberty

§ produced by gonadal glands (ovaries and testes)

§ fertility and reproduction

§ various other regulating functions

"male sex hormones": androgens

"female sex hormones": estrogens and progestogens

non-steroidal hormones: follicle-stimulating hormone, gonadotropin-releasinghormone,... (= glycoprotein hormones)

Jan DeskaBioorganicChemistry

Sturctural Comparison between the Sex Hormones

H

OH

HOH

H

estradiolH

OH

OH

H

testosterone

nuclear receptors show very high affinities (down to 50 pM) with no crosstalk

flat phenol region

H-bond donor

additional methyl and half boat conformation

H-bond acceptor

Jan DeskaBioorganicChemistry

Sturctural Comparison between the Sex Hormones

estradiol binding to its receptor

His524Arg394

Glu353

H2O

Leu387

Leu384

Jan DeskaBioorganicChemistry

Sturctural Comparison between the Sex Hormones

testosterone binding to its receptor

Arg766

Gln725

Met759

Met756

Jan DeskaBioorganicChemistry

Sturctural Comparison between the Sex Hormones

testosterone binding to its receptor

Arg766

Gln725

Met759

Met756

Jan DeskaBioorganicChemistry

Female-"specific" Hormone Pharmaceuticals

Jan DeskaBioorganicChemistry

Estrogen and progesterone receptors as target

DNA-bindingdomain

DNA hinge region ligandligand-binding domain

Jan DeskaBioorganicChemistry

Estrogen and progesterone receptors as target

both estrogenic and anti-estrogenic effects can be exploited

estradiol binds agonistic

blue helix fillsout the groove

coactivator canassociate to thedimericactivatedreceptor

H

OH

HOH

H

estradiol

Jan DeskaBioorganicChemistry

Estrogen and progesterone receptors as target

both estrogenic and anti-estrogenic effects can be exploited

tamoxifens bindsantagonistic

blue helix isrepelled by toobulky binder

coactivator incapableto coordinate andbind RNA polymerase

HO

O

4-hydroxytamoxifen

N

Jan DeskaBioorganicChemistry

Hormone Contraceptives

Menstrual Cycle

ovulationmenses

1 2 3 4 285 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

days of menstrual cycle

hormonelevels

ovariancycle

uterinecycle

egg developing follicle corpus luteum

§ combination ofestrogen andprogestogen modulateovarian cycle

§ estrogen supportsripening of egg andformation of follicles

§ progestogen supportsthe structure of theuterine lining(endometrium) andformation of thecervical mucus

estrogenprogestogen

FSHLH

ovary

uterus

cervix

H

OH

HOH

H

estradiolH

OH

H

progesterone

O

H

OH

HOH

H

estradiolH

OH

H

progesterone

O

Jan DeskaBioorganicChemistry

Hormone Contraceptives

Menstrual Cycle

ovulationmenses

1 2 3 4 285 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

days of menstrual cycle

hormonelevels

ovariancycle

uterinecycle

egg developing follicle corpus luteum

indirect effects

§ estrogen andprogestogen givenegative feedback tohypothalamus, modulating secretion ofgonadotropin-releasinghormone

§ GnRH lack decreasessecretion of follicle-secreting hormone(FSH) and luteinizinghormone (LH)

estrogenprogestogen

FSHLH

H

OH

HOH

H

estradiolH

OH

H

progesterone

O

ovary

uterus

cervix

H

OH

HOH

H

estradiolH

OH

H

progesterone

O

Jan DeskaBioorganicChemistry

Hormone Contraceptives

The "father of the pill"

Carl Djerassi (1923 – 2015)

§ chemist, novelist, playwriter

§ early steroid studies, e.g. conversion oftestosterone to estrone (aromatase-like reaction)

§ development of first oral contraceptive based on norethisterone (1956)

H

OH

OH

HH3C oxidation

– CO2H

OH

HOH

H

H

OH

OH

H

Jan DeskaBioorganicChemistry

Hormone Contraceptives

menses

1 2 3 4 285 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

days of menstrual cycle

hormonelevels

ovariancycle

uterinecycle

egg ... no follicle formation and ripening

Birth Control Pills

§ prevents ovulation

§ progestogen(gestagene) inhibitsimplantation of egg into uterine wall

§ additional effect ofprogestogens: thickening ofcervical mucus toprevent spermentering the uterus

§ combined administration of estrogen & progestogene or progestogen-only pills

Jan DeskaBioorganicChemistry

Hormone Contraceptives

Birth control pill

modern combined oral contraceptives based on synthetic analogues

estrogens progestins (= artificial progestogens)

H

O

HOH

H

estradiol cypionate

O

HHO

H

H

ethynylestradiol

OH

H

OH

OH

H

norethisterone

HO

H

H

drospirenone

O

O

Jan DeskaBioorganicChemistry

Hormone Contraceptives

Oral contraceptive pill vs. IUS (intruterine system)

hormone IUS copper IUS

Jan DeskaBioorganicChemistry

Hormone Contraceptives

Emergency contraceptives ("morning-after-pills")

H

OH

OH

H

levonorgestrel

H

progestin-type drugs

§ inhibit implantation of egg in endometrium(uterine lining)

Jan DeskaBioorganicChemistry

Hormone Contraceptives

Emergency contraceptives ("morning-after-pills")

H

OH

OH

H

levonorgestrel

H

progestin-type drugs

§ inhibit implantation of egg in endometrium(uterine lining)

Jan DeskaBioorganicChemistry

Hormone Contraceptives

Emergency contraceptives ("morning-after-pills")

H

OH

OH

H

levonorgestrel

H

HO

H

ulipristal acetate

O

O

O

N

progestin-type drugs

§ inhibit implantation of egg in endometrium(uterine lining)

antiprogestin-type drugs

§ progestogene receptor antagonists

§ (ulipristal acetate or mifepristone)

§ induce detachement of endometrium

Jan DeskaBioorganicChemistry

Anti-progestins in Medical Abortion

Combination of anti-progestin and synthetic prostaglandins

mifepristoneH

OH

O

H

N

+

HO

OOMe

O

OH

misoprostol

HO

OOMe

O

gemeprostHO

§ weakening of uterine lining

§ myometrial contraction (uterine smooth muscle) to expulse tissue

Jan DeskaBioorganicChemistry

Hormone Replacement Therapy

Treatment of menopause-related lack of estrogens by medication withestrogen receptor agonists

§ estrogen has multiple targets apart fromdirect reproductive organs

§ HRT reduces risk of coronary heartdiseases

§ HRT prevents bone loss andosteoporotic fractures

§ but: estradiol and first-generation estrogen mimics increase risk of breastcancer and endometrial tumors

H

OH

HOH

H

estradiol

diethylstilberolHO

OH

Jan DeskaBioorganicChemistry

Hormone Replacement Therapy

Selective estrogen receptor modulators (SERMs)

§ SERMs act as selective agonist in bonebut exhibit (partial) antagonistic activityin breast and/or uterus endometrialtissue

§ resistances found in stilbene-type anti-estrogens due to upregulation ofestrogen receptor phosphorylation

§ third-generation: fulvestrant

O

tamoxifen

N

S

O

OH

Oraloxifen

N

H

OH

HOH

H

SO O F F

F

FF

5

fulvestrant

Jan DeskaBioorganicChemistry

Aromatase Inhibitors

§ in pre-menopause, estrogen production occurs mainly in ovaries

§ post-menopause estrogen arises from aromatization of androgens in peripheraltissue, with little transport across the body

§ breast and ovarian cancer requires estradiol to grow

Jan DeskaBioorganicChemistry

Aromatase Inhibitors

§ in pre-menopause, estrogen production occurs mainly in ovaries

§ post-menopause estrogen arises from aromatization of androgens in peripheraltissue, with little transport across the body

§ breast and ovarian cancer requires estradiol to grow

§ aromatase inhibitors (AI's) limit supply of estrogens of the fast-growing tissues

H

O

OH

H

exemestane

(steroidal AI's)

OH

H

testolactone

O OCNCN

NNN

N

CN

CN

NN

anastrozole

(non-steroidal AI's)

letrozole

Jan DeskaBioorganicChemistry

Aromatase Inhibitors

§ in pre-menopause, estrogen production occurs mainly in ovaries

§ post-menopause estrogen arises from aromatization of androgens in peripheraltissue, with little transport across the body

§ breast and ovarian cancer requires estradiol to grow

§ aromatase inhibitors (AI's) limit supply of estrogens of the fast-growing tissues

§ in addition: used in treatment of male gynecomastia (benign growth of breast)

H

O

OH

H

exemestane

(steroidal AI's)

OH

H

testolactone

O OCNCN

NNN

N

CN

CN

NN

anastrozole

(non-steroidal AI's)

letrozole

Jan DeskaBioorganicChemistry

Aromatase Inhibitors

§ in pre-menopause, estrogen production occurs mainly in ovaries

§ post-menopause estrogen arises from aromatization of androgens in peripheraltissue, with little transport across the body

§ breast and ovarian cancer requires estradiol to grow

§ aromatase inhibitors (AI's) limit supply of estrogens of the fast-growing tissues

§ in addition: used in treatment of male gynecomastia (benign growth of breast)

H

O

OH

H

exemestane

(steroidal AI's)

OH

H

testolactone

O OCNCN

NNN

N

CN

CN

NN

anastrozole

(non-steroidal AI's)

letrozole

Jan DeskaBioorganicChemistry

Male-"specific" Hormone Pharmaceuticals

Jan DeskaBioorganicChemistry

Progesterone receptor in male contraception

Combination of progestogen and androgen can significantly suppress spermatogensis

§ native role of progesterone in malesunknown (other than source of testosterone

§ however, progestogen receptors found in male hypothalamus

§ negative feedback suppression ofgonadotropins reduces also follicle-stimulating hormone

§ low FSH levels suppress spermatogenesisproteins in Sertoli cells in the testes

Wang et al., J. Clin. Endocrinol. Metab. 2008, 93, 1774-1783.Page, Amory, Bremner, Endocrin. Rev. 2008, 29, 465-493.

HO

H

H

medroxyprogesterone acetate

O

O

O

H

OH

OH

HH

etonogestrel

Jan DeskaBioorganicChemistry

Androgen receptors as Pharma Targets

Agonistic binding of androgenic hormones (testosterone & dihydrotestosterone)

§ development of male sexual characteristics and regulation ofspermatogenesis

§ androgens support gain and maintenance of bone structure and skeletalmuscles

§ influence hair growth but likewise associated to pattern hair loss

H

OH

OH

H

testosteroneH

OH

OH

H

dihydrotestosteroneH

Jan DeskaBioorganicChemistry

Androgen receptors as Pharma Targets

Agonistic binding of androgenic hormones (testosterone & dihydrotestosterone)

§ development of male sexual characteristics and regulation ofspermatogenesis

§ androgens support gain and maintenance of bone structure and skeletalmuscles

§ influence hair growth but likewise associated to pattern hair loss

§ also: essential factor in normal female fertility (regulates ovulation)

H

OH

OH

H

testosteroneH

OH

OH

H

dihydrotestosteroneH

Jan DeskaBioorganicChemistry

Androgen receptors as Pharma Targets

Anabolic steroids as muscle and bone growth agent

§ synthetic androgens in the treatment ofgrowth failure diseases

§ bone marrow stimulation H

OH

OH

H

nandrolone

H

H

OH

OH

H

dianabol

H

OH

OH

H

drostanoloneH

Jan DeskaBioorganicChemistry

Androgen receptors as Pharma Targets

Anabolic steroids as muscle and bone growth agent

§ synthetic androgens in the treatment ofgrowth failure diseases

§ bone marrow stimulation

but also

§ performance enhancing drugs

• often illegal and not properly controlled

• neuropsychiatic effects (mood disorders, aggression, dependence)

• development of female sexual characteristics (conversion to estrogensby aromatase)

• liver and kidney failure

H

OH

OH

H

nandrolone

H

H

OH

OH

H

dianabol

H

OH

OH

H

drostanoloneH

Jan DeskaBioorganicChemistry

Androgen receptors as Pharma Targets

Androgen receptor antagonists

§ anti-androgens in treatment of prostate cancer

• side effects: reduced sexual activity (chemical castration)

HO

H

H

cyproterone acetateCl

O

O

O

NH

HO

H

H

finasterideH

ONH

§ anti-androgens in treatment of breast cancer

• over-expression of androgen receptors in malign breast tissue

• similar to SERMs, also female androgenic receptors can beaddressed to decrease tumor risk

SUMMARY

§ steroid hormone therapies as part of themost transformative developments formodern society

§ high specificity allows for nuclear receptorsto distinguish strikingly similar steroids withhigh fidelity

§ but: steroid metabolism can also changestructures and switch specificity from onereceptor to another

Jan DeskaBioorganicChemistry