Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.
Synthesis and in vitro activity of some epimeric 20 alpha-hydroxy, 20-oxime and aziridine pregnene derivatives as inhibitors of human 17 alpha-hydroxylase/C17,20-lyase and 5 alpha-reductase.
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一些差向异构 20 α-羟基、20-肟和氮丙啶孕烯衍生物的合成和体外活性，作为人 17 α-羟化酶/C17,20-裂合酶和 5 α-还原酶的抑制剂。
DOI：
10.1016/s0968-0896(98)00110-2
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发表时间：
1998
影响因子：
3.5
通讯作者：
Brodie,AM
中科院分区：
文献类型：
--
作者：
Ling,YZ;Li,JS;Kato,K;Liu,Y;Wang,X;Klus,GT;Marat,K;Nnane,IP;Brodie,AM
合成了孕酮的差向异构体20-羟基、20-肟、16α、17α、17，20和20，21-氮丙啶衍生物，并评价了它们对人17α-羟化酶/C17，20-裂解酶（P45017α）和5α-还原酶（5α-R）的抑制作用。重新研究了16-脱氢孕烯醇酮乙酸酯（3a）的还原。NaBH_4在CeCl_3存在下对20β-醇的立体选择性[20α/20β-OH（4α/4β）=1/2.7]优于文献报道的LTBAH法或Meerwein-Pondroff法，Zn在HOAc中还原仅生成20α-醇（4αB）。以4αB和4βB为原料，合成了20α和20β-羟基-4，16-孕甾二烯-3-酮（9α）和（9β）。还合成了20-肟孕甾二烯和16α，17 α，17，20和20，21-氮丙啶基-5-孕甾烯衍生物。LiAlH 4还原16-烯-20-肟（12 b）得到20（R）-（13 a）和20（S）-17，20-氮丙啶（13 b）以及20（R）-17，20-氮丙啶（14 a）。几种化合物抑制人P45017α的效力大于酮康唑。5α-R酶试验表明，（9α）没有任何活性，（9β）和（3b）是有效的5α-还原酶抑制剂（IC 50 =21和31 nM），活性与非那肽相似。20-肟（17 a）和（17 b）是5α-R（IC 50 =63和115 nM，相比之下，芬普胺为33 nM）和P45017α（IC 50 =43和25 nM，相比之下，酮康唑为78 nM）的强效双重抑制剂。
Some epimeric 20-hydroxy, 20-oxime, 16α, 17α-, 17,20- and 20,21-aziridine derivatives of progesterone were synthesized and evaluated as inhibitors of human 17α-hydroxylase/C17,20-lyase (P45017α) and 5α-reductase (5α-R). The reduction of 16-dehydropregenolone acetate (3a) was reinvestigated. NaBH4in the presence of CeCl3gave better stereoselectivity for 20β-ol [20α/20β-OH (4α/4β)=1/2.7] than LTBAH or the Meerwein–Pondroff method reported; reduction with Zn in HOAc formed exclusively 20α-ol (4αb). The 20α- and 20β-hydroxy-4,16-pregnadien-3-one (9α) and (9β) were synthesized from the alcohols 4αb and 4βb. Several 20-oxime pregnadienes and 16α,17α-, 17,20- and 20,21-aziridinyl-5-pregnene derivatives were also synthesized. LiAlH4reduction of the 16-en-20-oxime (12b) yielded 20 (R)-(13a) and 20(S)-17α,20-aziridine (13b) and 20(R)-17β,20-aziridine (14a). Several compounds inhibited the human P45017αwith greater potency than ketoconzole. The 5α-R enzyme assay showed that while (9α) did not have any activity, (9β) and (3b) were potent 5α-reductase (IC50=21 and 31nM) inhibitors with activities similar to finasteride. The 20-oximes (17a) and (17b) were potent dual inhibitors for both 5α-R (IC50=63 and 115nM, compared to 33nM for finasteride) and P45017α(IC50=43 and 25nM, compared to 78nM for ketoconazole).