Chemistry - The Medicinal Chemistry of Antihormonal Agents

Question 1

What are steroids, what is their role and what types are there?

Answer 1

Biosynthesised from cholesterol
Androgens, estrogens and progestogens
Role: tissue specific growth promoters

Question 2

Describe (and draw) the structure of a steriod

Answer 2

4 rings A-D

Question 3

Where do most breast tumours normally derive from and what characteristic arises from this?

Answer 3

Normally derived from normal breast tissue and often incorporate estrogen receptors (ERs).

Question 4

What does the rate of an ER+ tumour depend on?

Answer 4

Estrogen levels

Question 5

What determines the treatment options for breast cancer?

Answer 5

Staging of the disease, ER+ v ER-
Pre or post menopausal patient

Surgery, chemo, radiotherapy, biological or hormonal therapies all important

Question 6

Which two main anti-hormonal strategies are employed in treatment?

Answer 6

Inhibition of estrogen biosynthesis (steroid synthesis)

Estrogen receptor antagonists (ER+ tumour)

Question 7

Which drug is involved in estrogen receptor antagonism?

Answer 7

Tamoxifen (TAM)

Question 8

What is the target of inhibiting estrogen synthesis?

Answer 8

Aromatase (CYP450 enzyme)

Question 9

How does anastrazole work? What is its target?

Answer 9

Triazole ring important to function, top N can form a strong covalent bond.
Sits in the aromatase active site and binds strongly, preventing its crucial role in the synthesis of estrogen.

Question 10

What is exemestane?

Answer 10

Looks like a steroid
Good inhibitor because forms a exocyclic double bond
Becomes activated in the active site of aromatase and forms a covalent bond
Suicide inhibitor, non reversible

Question 11

Is anastrazole or letrozole effective in pre-menopausal women?

Answer 11

No, their estrogen inhibition isn’t effective because the bodies natural negative feedback system creates more estrogen.
In post-menopausal women this feedback control is not present.