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