Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17α- hydroxylase-C17,20-lyase (P450(17α)): Potential agents for the treatment of prostate cancer

Vincent C O Njar, Katsuya Kato, Ivo P. Nnane, Dmitry N. Grigoryev, Brian J. Long, Angela M H Brodie

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)902-912
Number of pages11
JournalJournal of Medicinal Chemistry
Volume41
Issue number6
DOIs
StatePublished - Mar 12 1998
Externally publishedYes

Fingerprint

Lyases
Cytochromes
Mixed Function Oxygenases
Prostatic Neoplasms
Steroids
Azoles
Nucleophiles
Ketoconazole
Bioactivity
Heme
Cell culture
Androgens
Rats
Oxidoreductases
Substitution reactions
Nitrogen
Iron
Cells
Enzymes
Cell Line

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17α- hydroxylase-C17,20-lyase (P450(17α)) : Potential agents for the treatment of prostate cancer. / Njar, Vincent C O; Kato, Katsuya; Nnane, Ivo P.; Grigoryev, Dmitry N.; Long, Brian J.; Brodie, Angela M H.

In: Journal of Medicinal Chemistry, Vol. 41, No. 6, 12.03.1998, p. 902-912.

Research output: Contribution to journalArticle

Njar, Vincent C O ; Kato, Katsuya ; Nnane, Ivo P. ; Grigoryev, Dmitry N. ; Long, Brian J. ; Brodie, Angela M H. / Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17α- hydroxylase-C17,20-lyase (P450(17α)) : Potential agents for the treatment of prostate cancer. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 6. pp. 902-912.
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abstract = "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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