Li X, Singh S M, Labrie F
Medicinal Chemistry Division, CHUL Research Center, Québec, Canada.
J Med Chem. 1995 Mar 31;38(7):1158-73. doi: 10.1021/jm00007a013.
A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)3/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC50s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50s = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM). Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC50s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50s < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107).(ABSTRACT TRUNCATED AT 400 WORDS)
从17β-羟基-4-氮杂甾体合成了一系列17β-（N-烷基/芳基甲酰胺基）-和17β-[(N-烷基/芳基)烷基/芳酰胺基]-3-氧代-4-氮杂-5α-甾体，并评估了它们作为人5α-还原酶抑制剂和雄激素受体拮抗剂的活性。17β-羟基化合物经琼斯氧化得到17-酮基-4-氮杂甾体，将其与胺及NaBH(OAc)3/NaBH3CN反应，得到17β-（N-烷基/芳基氨基）-4-氮杂甾体10 - 27。另外，上述化合物也可由胺与17-酮基-4-氮杂甾体反应形成亚胺，然后用NaBH4还原制得。胺10 - 27的甲酰化反应得到17β-（N-烷基甲酰胺）28 - 41；然而，酰化反应则得到17β-[(N-烷基/芳基)烷基/芳酰胺]42 - 53。与N,N-二乙基-4-甲基-3-氧代-4-氮杂-5α-雄甾烷-17β-甲酰胺（4-MA；IC50 = 4.15 nM）相比，17β-（N-烷基甲酰胺基）-4-氮杂甾体是人类I型5α-还原酶的强效抑制剂，化合物29、30、36和37的IC50值分别测定为3.05、0.91、2.19和2.35 nM。构效关系表明，I型酶对四至五个碳原子的N-取代直链烷基侧链具有偏好性。另一方面，甲酰胺32（N-庚基）和33（N-辛基），除了抑制I型酶（IC50分别为9.57和16.9 nM）外，与N-（1',1'-二甲基乙基）-3-氧代-4-氮杂-5α-雄甾-1-烯-17β-甲酰胺（MK-906；IC50 = 4.53 nM）相比，对人类II型5α-还原酶也表现出较强的抑制活性（IC50分别为14.0和18.4 nM）。该系列中的其他化合物对II型酶表现出中等活性（IC50 > 100 nM）。17β-[(N-烷基/芳基)烷基/芳酰胺]45、46、48和51对人类I型5α-还原酶表现出高效抑制活性，IC50分别为1.77、2.42、2.93和5.44 nM；而对II型酶观察到中等至无作用（100 < IC50 < 1000 nM），化合物48除外（IC50 = 3.75 nM）。在另一种取代模式中，研究了N-芳基/烷基酰胺；与母体化合物50相比，供电子基团增加了化合物51的活性，而吸电子基团降低了化合物52和53的活性。除了它们的5α-还原酶活性外，还研究了17β-（N-烷基甲酰胺）对二氢睾酮（DHT）刺激的雄激素敏感的日本住友小鼠乳腺癌细胞（克隆SEM-107）增殖的抑制活性。（摘要截断于400字）
