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首页> 外文期刊>Journal of Medicinal Chemistry >Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2 alpha-functionalization of 25-dehydro-1 alpha-hydroxyvitamin D-3-26,23-lactones
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Further synthetic and biological studies on vitamin D hormone antagonists based on C24-alkylation and C2 alpha-functionalization of 25-dehydro-1 alpha-hydroxyvitamin D-3-26,23-lactones

机译：基于25-脱氢-1α-羟基维生素D-3-26,23-内酯的C24-烷基化和C2α-官能化的维生素D激素拮抗剂的进一步合成和生物学研究

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An efficient synthesis and the biological evaluation of 80 novel analogs of 25-dehydro-1 alpha-hydroxyvitamin D3-26,23S-lactone 2 (TEI-9647) and its 23R epimer (3) in which the lactone ring was systematically functionalized by introduction of a C-1 to C-4 primary alkyl group at the C24 position (5 sets of 4 diastereomers), together with their C2 alpha-methyl, 3-hydroxypropyl, and 3-hydroxypropoxy-substituted derivatives were described. The triene structure of the vitamin D-3 was constructed using palladium-catalyzed alkenylative cyclization of the A-ring precursor enyne with the CD-ring counterpart bromoolefin having the C24-alkylated lactone moiety on the side chain. The CD-ring precursors having 23,24-cis lactones were prepared by using a chromium-mediated syn-selective allylation-lactonization process, and the 23,24-trans lactone derivatives were derived from these via inversion of the C23 stereochemistry. The biological evaluation revealed that both binding affinity for chick vitamin D hormone receptor and antagonistic activity (inhibition of vitamin D hormone induced HL-60 cell differentiation) were affected by the orientation and chain-length of the primary alkyl group on the lactone ring. Furthermore, the C2 alpha-functionalization of the C24-alkylated vitamin D3 lactones dramatically enhanced their biological activities. The most potent compound to emerge, (23S, 24S)-2R-(3-hydroxypropoxy)-24-propyl exhibited almost 1000-fold stronger antagonistic activity (IC50 = 7.4 pM) than 2 (IC50 = 6.3 nM).
机译：有效合成和生物学评价80-新型25-脱氢-1α-羟基维生素D3-26,23S-内酯2（TEI-9647）及其23R差向异构体（3）的内酯环通过引入被系统地功能化描述了在C24位置的C-1至C-4伯烷基（5组4个非对映异构体），以及它们的C2α-甲基，3-羟丙基和3-羟基丙氧基取代的衍生物。维生素D-3的三烯结构是通过A环前体烯炔的钯催化烯基环化和侧链上具有C24烷基化内酯部分的CD环对应的溴烯烃而构建的。通过使用铬介导的顺-选择性烯丙基化-内酯化方法制备具有23,24-顺式内酯的CD-环前体，并且通过反转C23立体化学从中衍生出23,24-反式内酯衍生物。生物学评估表明，对鸡维生素D激素受体的结合亲和力和拮抗活性（抑制维生素D激素诱导的HL-60细胞分化）都受内酯环上伯烷基的方向和链长的影响。此外，C24烷基化的维生素D3内酯的C2α-官能化大大增强了它们的生物学活性。出现的最有效的化合物（23S，24S）-2R-（3-羟基丙氧基）-24-丙基的拮抗活性（IC50 = 7.4 pM）比2（IC50 = 6.3 nM）强近1000倍。

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