title: Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer.
abstract: Steroidal compounds having a 17-(3-pyridyl) substituent together with a 16,17-double bond have been synthesized, using a palladium-catalyzed cross-coupling reaction of a 17-enol triflate with diethyl(3-pyridyl)borane, which are potent inhibitors of human testicular 17 alpha-hydroxylase-C17,20-lyase. The requirement for these structural features is stringent: compounds having 2-pyridyl (9), 4-pyridyl (10), or 2-pyridylmethyl (11) substituents instead of the 3-pyridyl substituent were either poor inhibitors or noninhibitory. Reduction of the 16,17-double bond to give 17 beta-pyridyl derivatives diminished potency with 3-pyridyl substitution (3-->27; IC50 for lyase, 2.9-->23 nM) but increased it with a 4-pyridyl substituent present (10-->28; IC50 1 microM-->53 nM). In contrast, a variety of substitution patterns in rings A-C of the steroid skeleton afforded inhibitors having potencies similar to those most closely related structurally to the natural substrates pregnenolone and progesterone, respectively 17-(3-pyridyl)androsta-5,16-dien-3 beta-ol (3, Kiapp < 1 nM; IC50 for lyase, 2.9 nM) and 17-(3-pyridyl)androsta-4,16-dien-3-one (15; IC50 for lyase, 2.1 nM). Thus compounds having variously aromatic ring A (18), saturated rings A/B (21, 22), and oxygenated ring C (26) exhibited IC50 values for lyase (1.8-3.0 nM) falling within a 2-fold range. The most potent compounds are candidates for development as drugs for the treatment of hormone-dependent prostatic carcinoma.
authors.affiliation: Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, U.K.
authors.forename: G A
authors.initials: GA
authors.lastname: Potter
authors.forename: S E
authors.initials: SE
authors.lastname: Barrie
authors.forename: M
authors.initials: M
authors.lastname: Jarman
authors.forename: M G
authors.initials: MG
authors.lastname: Rowlands
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D013256:Steroids; D013254:Steroid 17-alpha-Hydroxylase; C022433:pregnenolone 17-alpha-hydroxylase