Synthesis and biological evaluation of 3-(azolylmethyl)-1H-indoles and 3-(α-azolylbenzyl)-1H-indoles as selective aromatase inhibitors

Figures & data

Figure 1 Structures of nonsteroidal inhibitors.

Table I.  Inhibition of aromatase by major nonsteroidal inhibitors.

compound	P450 arom inhibition [23] IC50 (nM)	material
aminoglutethimide	3,800.000	Human placenta
MPV-2213ad	0,180.000	Human placenta
anastrozole	14.600	Human placenta
fadrozole	6.910	Human placenta
letrozole	0.390	Human placenta
vorozole	1.400	Rat granulosa cells
YM-511	0.125	Human placenta

Figure 2 Structures and aromatase inhibitory activities of compounds ML60, PI19 and CLE36.

Scheme 1 Synthetic route to 3-azolylmethyl-1H-indoles 11–14. Reagents: (a) see reference [34]; (b) K₂CO₃, acetone, RCl; (c) NaBH₄, methanol; (d) CDI, THF; (e) SDT, CH₃CN.

Scheme 2 Synthetic route to 3-(azolylbenzyl)-1H-indoles 30–37. Reagents: (a) see reference [33]; (b) AlCl₃, CH₂Cl₂, ArCOCl; (c) CsCO₃, CH₃CN, R₁Cl; (d) NaBH₄, methanol; (e) CDI, THF; (f) SDT, CH₃CN.

Table II.  Inhibition of P450 arom and P450 17α by 3-(azolylmethyl)-1H-indoles 11–18.

			P450 arom		P450 17α
compound	R	Het	IC50 (μM)^a	RP^b	% inhibition^c
11	2-chlorobenzyl	imidazol-1-yl	0.054	342.6	62.8
12	2-fluorobenzyl	imidazol-1-yl	0.124	149.2	55.5
13	3-fluorobenzyl	imidazol-1-yl	0.082	225.6	70.2
14	4-cyanobenzyl	imidazol-1-yl	0.050	370.0	15.4
15a	2-chlorobenzyl	triazol-1-yl	0.173	106.9	9.3
15b	2-chlorobenzyl	triazol-4-yl	3.500	5.3	0.0
16a	2-fluorobenzyl	triazol-1-yl	0.420	44.0	0.0
16b	2-fluorobenzyl	triazol-4-yl	7.220	2.6	0.5
17	3-fluorobenzyl	triazol-1-yl	0.307	60.3	14.4
18	4-cyanobenzyl	triazol-1-yl	0.141	131.2	1.8

^a IC₅₀ is the concentration of inhibitor required to give 50% inhibition. Concentration of testosterone: 2.5 μM. The given values are mean values of at least three experiments. The deviations were within ± 5%.

^b Relative potency, calculated from the IC₅₀ values and related to AG (IC₅₀ of AG: 18.5 μM).

^c Concentration of progesterone: 25 μM. Concentration of inhibitor: 2.5 μM. All values are the mean of at least 2 determinations.

Table III.  Inhibition of P450 arom and P450 17α by 3-(α-azolylbenzyl)-1H-indoles 30–37.

compound	R	X	Het	IC50 (μM)^a	RP^b	% inhibition^c
30	ethyl	4-F	imidazol-1-yl	0.052	357.1	3.7
31	ethyl	2,4-diCl	imidazol-1-yl	0.333	55.6	0.7
32^d	2-chlorobenzyl	4-F	imidazol-1-yl	0.964	19.2	1.6
33	4-fluorobenzyl	4-F	imidazol-1-yl	0.623	29.7	0.0
34	ethyl	4-F	triazol-1-yl	0.980	18.9	0.9
35	ethyl	2,4-diCl	triazol-1-yl	4.400	4.2	0.0
36	2-chlorobenzyl	4-F	triazol-1-yl	< 25	-	0.0
37	4-fluorobenzyl	4-F	triazol-1-yl	7.1	2.6	1.0

^a IC₅₀ is the concentration of inhibitor required to give 50% inhibition. Concentration of testosterone: 2.5 μM. The given values are mean values of at least three experiments. The deviations were within ± 5%.

^b Relative potency, calculated from the IC₅₀ values and related to AG (IC₅₀ of AG: 18.5 μM).

^c Concentration of progesterone: 25 μM. Concentration of inhibitor: 2.5 μM. All values are the mean of at least 2 determinations.

^d Tested as nitrate.

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