Medicinal Chemistry of Antihormonal Agents Flashcards
What are the sex hormones? What are they biosynthesised from?
- Progestogens, Androgens, Estrogens
- Biosynthethised from cholesterol
What is the purpose of sex hormones?
They act as tissue-specific growth promoters
How many carbons does the precursor cholesterol (steroid) have? What enzyme is responsible for cleavage?
- C27
- CYP450 Aromatase enzyme
What are the incremental steps for cleavage of cholesterol to pregnanes, androgens and estrogens?
- C27 cholesterol > Aromatase activity - C21 pregnane (parent of progesterone) > Aromatase activity - C19 androgens > Aromatase activity - C18 estrogens
How prevalent is breast cancer, and what circumstances make it suitable for antihormonal therapy?
- Most common cancer in the UK
- Typically derived from normal breast tissue; 2/3 will be ER+
- If tumour is ER+; growth likely to be influenced by estrogen levels
- Thus a candidate for antihormonal therapies
What are the two possible targets for antihormonal therapy in breast cancer?
- Inhibition of estrogen biosynthesis (aromatase inhibitors) = no stimulation of ER+ve tumour
- Estrogen receptor antagonists (Tamoxifen) = inhibit receptors at target/tumour site
What factors determine treatment options for breast cancer?
- Staging of disease
- ER+ vs. ER-
- Pre vs post-menopause
Give an example of an estrogen receptor antagonist. How does it work?
- Tamoxifen
- Stops binding of diethylbestrol (DES) ligand; competitive inhibition of ER
What is the mechanism of action of Tamoxifen?
1) Metabolism to 4-OH Tamoxifen (4-hydroxy metabolite)
2) Binding to estrogen receptor
3) Conformational change prevents binding of co-activators
What occurs in the normal binding of DES to ER, and how does Tamoxifen prevent this in its own binding?
- Diethylstilbestrol is the normal substrate for ER
- Upon DES binding, co-activator is recruited which binds to ER, as Helix-12 is in an ‘open’ conformation
- Triggers downstream signalling
- Tamoxifen (4-hydroxytamoxifen) binds (also a substrate for ER), but is larger substrate than DES; Helix-12 cannot remain in ‘open’ position whilst TAM is bound
- Conformational change, Helix-12 flips over (to where co-activator would normally occupy) to accommodate TAM
- Thus co-activator cannot be recruited (change in 3D structure)
- Thus no signalling, no downstream effect, no ER activation.
Why is Tamoxifen a pro-drug? Why is there a stronger binding affinity after hydroxylation?
- Tamoxifen OG has little affinity to ER
- But when metabolised to 4-OH form (4-hydroxytamoxifen) by CYP450 enzymes (2D6/3A4), it has a 30-100x stronger binding affinity for ER
- Hydroxylated metabolite more closely mimics phenolic A-ring in estrogen (-OH)
What chemical group of Tamoxifen induces Helix-12’s conformational change?
- Diethylamino side chain
- Bulky chemical group not present in agonist ligands, DES etc.
What is peculiar re. Tamoxifen’s structure?
- Looks like a steroid a bit; like estrone
- But has bulky diethylamino group etc.
How does aromatase enzyme’s (CYP450) structure allow oxidation (thus cleavage) of cholesterol to the estrogen end product?
- 3 sequential oxidations to reach estrogen
- Haem (Fe2+) group in centre; readily oxidises things
- Steroid hormone is bound to aromatase; spatially close to Fe2+ to be cleaved (oxidised)
What are the steps that take place between each cleavage by aromatase from androgen (C19) to estrogen (C18)?
- Methyl (-CH3) group of androgen is close in space to haem; methyl is oxidised to alcohol (-OH)
- Alcohol group is then oxidized again by Fe2+ haem to ketone
- Alpha-beta unconjugated ketone tautomerizes to enol form (keto-enol tautomerism)
- Enol form not favoured; but Haem oxidises again allowing cleavage of whole ketone group and aromatising of A-ring
= Estrogen (C18, now the ketone is cleaved)
