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Pharmacophore identification and 3D-QSAR study of a

series of biphenylmethylene derivatives

Androgens are well- known to stimulate prostate cancer (PC) growth. Androgen receptor

antagonists (anti-androgens) are commonly employed in combination with GnRH analogues

to prevent adrenal androgens from unfolding activity. This is the current standard therapy, the

so called combined androgen blockade (CAB). However, long-term application of

antagonists induces mutations of androgen receptor that render the receptor not to be

activated by the anti-androgenic drug or by endogenous glucocorticoids, resulting in

resistance to CAB. To avoid the stimulation, the inhibition of 17 - hydroxylase-17, 20-lyase

(CYP17) was proposed as a superior alternative to CAB. CYP17 catalyzes not only the

testicular but also the adrenal conversion of pregnenolone and progesterone to the weak

androgens DHEA and androstenedione, respectively. Testosterone subsequently formed from

these two weak androgens is in the prostate converted to DHT, which is the most potentandrogen. This final step of androgen activation can be inhibited by 5 -reductase (5-R)

inhibitors. However, CYP17 inhibition should be a better strategy than 5-R inhibition, as it

totally blocks not only androgen biosynthesis in testes and adrenals but also intracellular

androgen formation in the cancer cell. Thus, blockade of androgen production in testes and

adrenals by CYP17 inhibition is a promising strategy for the treatment of PC.

Hartmann et. al have synthesized a series of biphenylmethylene heterocycles as CYP17

inhibitors with the general formula given below in which heterocycle can be imidazole or

pyridine ring.

Heterocycle

R5

R1

R2

R3

R4

The general structure for all the molecules is shown in which the fusion of the biphenyl group

may not be present as in some molecules. R indicates different substituent.

A set of molecules have been selected for pharmacophore identification 3D-QSAR study with

an activity range spanning atleast 3 log fold with a wide structural diversity.

The selected compounds,

1. Belongs to the same congeneric series (Biphenylmethylene derivatives).2. Have same mechanism of action, inhibition of CYP17 (17 - hydroxylase-17, 20-

lyase) with mode of binding also being same.

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3. The parameters used are measured under identical conditions from the samelaboratory for all the compounds.

4. The activity for all the compounds is given in nm as IC50 for CYP17 inhibition.5. The activity range was found to be spanning atleast 3 log fold with the IC 50 of most

active compound being 37nm (no.29) and least active compound 10000nm (no. 38and MYP).

No. IC50(nm) No. IC50(nm)

1 1610 22 2300

2 4040 23 3100

3 408 24 2000

4 97 25 2200

5 1790 26 62

6 386 27 56

7 1370 28 75

8 577 29 37

9 647 30 493

10 760 31 1458

11 2000 32 38

12 438 33 75

13 164 34 3800

14 52 35 1400

15 188 36 388

16 217 37 118

17 310 38 10000

18 300 ABT 72

19 2100 KTZ 2780

20 1050 MYP 10000

21 790

Courtesy: - Hartmann et. al

Table1. IC50 values for inhibition of CYP17. ABT-Abiraterone, KTZ-Ketoconazole, MYP-Metyrapone

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CH3

O

CH3

N

OH

N

NH2

N

H

N

OH

N

O

NH2

N

F

1 2 3 4 5 6N

H

NH

O O

CH3

CH3

CH3

N

S

N

S

N

N

H

N

O

CH3 7 8 9 10 11

N

OH

NN

CH3

H

H

OH

NN

CH3

OH

H

OH

F

NN

CH3

OCH3

NN

CH3

Cl

OH

12 13 14 15 16

NN

CH3 CH3

NN

CH3

NN

CH3

CH3

NN N

N

17 18 19 20 21

NN

NN

CH3

SCH3

NN

CH3

CH3

NN

CH3

N

O 22 23 24 25

N

CH3CH3

OH

N

CH3 CH2

OH N

CH3 CH2

F

OH

N

CH3 CH2

OH

OH 26 27 28 29

N

CH3 CH2

NH

O O

CH3

CH3

CH3

N

CH3 CH2

NHO

OCH3CH3

CH3N

CH3 CH2

NH2N

CH3 CH2

NH2

NH2

30 31 32 33

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NN

F

CH3CH3

NN

H

CH2

NN

H

H

NN

F

CH3

NH

34 35 36 37

N

NH

NH

O O

CH3

CH3

CH3

O

OCH3CH3

CH3

N

CH3

CH3

OH

O

O

O

N

N

O

CH3

N

N

Cl

Cl

N

O

N

CH3

CH3

38 ABT KTZ MYP

Figure1. Structures of compounds mentioned in table1.