Efficient access to novel androsteno-17-(1′,3′,4′)-oxadiazoles and 17β-(1′,3′,4′)-thiadiazoles via N-substituted hydrazone and N,N′-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro
Efficient access to novel androsteno-17-(1′,3′,4′)-oxadiazoles and 17β-(1′,3′,4′)-thiadiazoles via N-substituted hydrazone and N,N′-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro
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DOI：
10.1016/j.ejmech.2015.05.010
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发表时间：
2015-06-15
影响因子：
6.7
通讯作者：
Frank, Eva
中科院分区：
文献类型：
--
作者：
Kovacs, Dora;Woelfling, Janos;Frank, Eva
以孕烯醇酮乙酸酯和孕二烯醇酮乙酸酯为原料，通过多步途径有效合成了Delta(5)雄烯系列中的一系列新型17-外型恶二唑和噻二唑。通过苯碘鎓二乙酸盐诱导衍生自 3 β-乙酰氧基-和 3 β-羟基雄雄-5-烯-17 β-甲醛的缩氨基脲和 N-酰腙的氧化闭环，高产率地获得了 17 β-(1',3',4')-恶二唑。为了合成类似的 Delta(16)-17-恶二唑基衍生物，由 4-乙酰氧基雄雄-5,16-二烯-17-甲酸制备 N,N'-二取代肼中间体，然后在 POCl3 存在下进行环化脱水。使用 Lawesson 试剂将含有饱和环 D 的甾族 N,N' 二酰肼环化，以良好的收率得到 17 个 β-(1',3',4')-噻二唑。大多数产品在基础培养基中进行脱乙酰化，以扩大可用于药理学研究的化合物库。通过 MU 测定，在体外筛选所有这些衍生物对四种恶性人贴壁细胞系（HeLa、A2780、MCF7 和 A431）的抗增殖作用。新合成的17-外杂环的3个β-羟基衍生物在体外进行了测试，以研究其对大鼠睾丸C-17,C-20-Iyase的抑制作用。其中一种 1,3,4-恶二唑基衍生物被证明具有显着的酶抑制作用，其 IC30 (0.065 μM) 与阿比特龙处于同一数量级。 (C) 2015 Elsevier Masson SAS。版权所有。
A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Delta(5) androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17 beta-(1',3',4')-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3 beta-acetoxy- and 3 beta-hydroxyandrost-5-ene-17 beta-carbaldehydes. For the synthesis of analogous Delta(16)-17-oxadiazolyl derivatives, N,N'-disubstituted hydrazine intermediates were prepared from 4-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3. The cyclization of steroidal N,N'diacylhydrazines containing a saturated ring D with the Lawesson reagent afforded 17 beta-(1',3',4')-thiadiazoles in good yields. Most of the products were subjected to deacetylation in basic media in order to enlarge the compound library available for pharmacological studies. All of these derivatives were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines (HeLa, A2780, MCF7 and A431) by means of the MU assay. The 3 beta-hydroxy derivatives of the newly-synthesized 17-exo-heterocycles were tested in vitro to investigate their inhibitory effects on rat testicular C-17,C-20-Iyase. One of the 1,3,4-oxadiazolyl derivatives proved to exert noteworthy enzyme-inhibitory action, with an IC30 (0.065 mu M) of the same order of magnitude as that of abiraterone. (C) 2015 Elsevier Masson SAS. All rights reserved.