TY - JOUR
T1 - Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17α- hydroxylase-C17,20-lyase (P450(17α))
T2 - Potential agents for the treatment of prostate cancer
AU - Njar, Vincent C.O.
AU - Kato, Katsuya
AU - Nnane, Ivo P.
AU - Grigoryev, Dmitry N.
AU - Long, Brian J.
AU - Brodie, Angela M.H.
PY - 1998/3/12
Y1 - 1998/3/12
N2 - A new synthetic route to a variety of novel Δ16-17-azolyl steroids is described: it involves the nucleophilic vinylic 'addition-elimination' substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some of these novel Δ16-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overall yields, are very potent inhibitors of human and rat testicular P450(17α). They are shown to be noncompetitive and appear to be slow-binding inhibitors of human P450(17α). The most potent compounds are 3β-hydroxy-17-(1H-imidazol-1-yl)androsta- 5,16-diene (17), 3β-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with K(i) values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (K(i) = 38 nM). Spectroscopic studies with a modified form of human P450(17α) indicate that the inhibition process involves binding of steroidal azole nitrogen to the heme iron of the enzyme. Furthermore, some of these potent P450(17α) inhibitors (27-29) are also powerful inhibitors of steroid 5α-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressive dual biological activities make them strong candidates for development as therapeutic agents for treatment of prostate cancer and other disease states which depend on androgens.
AB - A new synthetic route to a variety of novel Δ16-17-azolyl steroids is described: it involves the nucleophilic vinylic 'addition-elimination' substitution reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some of these novel Δ16-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overall yields, are very potent inhibitors of human and rat testicular P450(17α). They are shown to be noncompetitive and appear to be slow-binding inhibitors of human P450(17α). The most potent compounds are 3β-hydroxy-17-(1H-imidazol-1-yl)androsta- 5,16-diene (17), 3β-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with K(i) values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (K(i) = 38 nM). Spectroscopic studies with a modified form of human P450(17α) indicate that the inhibition process involves binding of steroidal azole nitrogen to the heme iron of the enzyme. Furthermore, some of these potent P450(17α) inhibitors (27-29) are also powerful inhibitors of steroid 5α-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressive dual biological activities make them strong candidates for development as therapeutic agents for treatment of prostate cancer and other disease states which depend on androgens.
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U2 - 10.1021/jm970568r
DO - 10.1021/jm970568r
M3 - Article
C2 - 9526564
AN - SCOPUS:0032510321
SN - 0022-2623
VL - 41
SP - 902
EP - 912
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 6
ER -