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Abiraterone acetate is a potent inhibitor of human cytochrome P450c17 (CYP17A1, 17α-hydroxylase/17,20-lyase) and is clinically used in combination with prednisone for the treatment of castration-resistant prostate cancer. Although many studies have documented the potency of abiraterone (Abi) in a variety of in vitro and in vivo systems for several species, the exact potency of Abi for human CYP17A1 enzyme has not yet been determined, and the structural requirements for high-potency steroidal azole inhibitors are not established. We synthesized 4 Abi analogs differing in the A-B ring substitution patterns: 3α-hydroxy-Δ4-Abi (13), 3-keto-Δ4-Abi (11), 3-keto-5α-Abi (6), and 3α-hydroxy-5α-Abi (5). We measured the spectral binding constants (Ks) using purified and modified human CYP17A1 along with the determination constants (Ki) applying a native human CYP17A1 enzyme in yeast microsomes for these compounds as well as for ketoconazole. For Abi, 3-keto-Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi, the type 2 spectral changes gave the best fit for a quadratic equation, since in these experiments Ks values were 0.1-2.6 nM, much lower than that for ketoconazole and 3α-hydroxy-Δ4-Abi (Ks values were 140 and 1660 nM, respectively). Inhibition experiments showed mixed inhibition patterns with Ki values of 7-80 nM. Abi dissociation from the CYP17A1-Abi complex was incomplete and slow; the t1/2 for dissociation was 1.8 hour, with 55% of complex remaining after 5 hours. We conclude that Abi and the 3 related steroidal azoles (3-keto-Δ4-Abi, 3-keto-5α-Abi, and 3α-hydroxy-5α-Abi), which also mimic natural substrates, are extraordinarily potent inhibitors of human CYP17A1, whereas the 3α-hydroxy-Δ4-Abi is moderately potent and comparable to ketoconazole.

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The objective of this study is to synthesize new steroidal compounds based on the progesterone skeleton with a high inhibitory activity for the enzyme 5alpha-reductase. Presently similar compounds are being used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, bening prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. (1)), a 5alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 8 (Fig. (4)) a 5alpha-reductase inhibitor has grately alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory we recently synthesized several new 16beta-methyl-pregnadiene-3,20-diones derivatives 27 (Fig.(6)), 38-42 (Fig. (11)), 16beta-phenyl-pregnadiene-3,17a-dione derivatives 32-33 (Fig. (7)), 16beta-phenyl-pregnatriene-3,17a-diones, 30, 31 (Fig. (7)) and 16beta-methyl-pregnatriene-3,20-diones 43-46 (Fig. (11)). These compounds were evaluated as 5alpha-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [(3)H]T to [(3)H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. All trienones 30, 31, and 43-46 in all biological models showed consistently a higher 5alpha-reductase inhibitory activity than the corresponding dienones 27, 32, 33 and 38-42. We believe that with these compounds the 5alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme and thus show a higher inhibitory activity.

Ten new 2,6,7-trioxabicyclo[2.2.2]octane derivatives, RC(OCH2)&R' [where R = H, R' = NOz R = H, R' = CH;OSO2C7H, (10); R CH3, R' = COOCH, (13); R = CH3, R' = COOC2H5 (14); R = CH,, R' = NO2 (15); and R = CH3, R' = NH2 (1611, were synthesized, and six other derivatives, 1-4, 11, and 12, were prepared by literature directions. Each of these bicyclic compounds was polymerized with boron trifluoride etherate as initiator at 0 "C. The polymers were usually obtained as highly crystalline white powders with high melting points accompanied by decomposition. These polymers were not soluble in any solvent without decomposition. Initiation with deliberately high initiator concentration gave soluble oligomers with T~~~ ca. 0.1 g/dL, indicating that most of the polymers had fairly high molecular weights. From IR and NMR spectroscopic results (of the oligomers) they possessed the structure (5); R = H, R' = NH2 (6); R = H, R' = N(CH3)Z (7); R = H, R' = NHCOCHS (8); R = H, R' = COOC2HS (9); IntroductionWith the objective of synthesizing linear stereoregular, high molecular weight analogues of polysaccharides, we have studied bicyclic orthoesters 2,6,7-trioxabicyclo-[2.2.l] heptane,' 2,7,8-trioxabicyclo[3.2.1]octane,2 and 2,8,9-trioxabicyclo[3.3.1]nonane.2 However, no stereoregular propagation has been observed. The molecular weight of these polymers has been low, and the polymers have all been liquid rubbers.The highly symmetrical 2,6,7-trioxabicyclo[2.2.2]octane system (1) has not been studied extensively before. Steuck3 showed that the 4-methyl derivative 2 underwent cationic polymerization. Bailey, Endo, and Saigo4 polymerized several derivatives of 1 with boron trifluoride at elevated temperatures to open both rings, causing volume expansion. In the present paper, we describe the synthesis and polymerization of 2,6,7-trioxabicyclo[2.2.2]octane (1) and its derivatives 2-16.