New androst-4-en-17-spiro-1,3,2-oxathiaphospholanes. Synthesis, assignment of absolute configuration and in vitro cytotoxic and antimicrobial activities

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• 作者：Natalija M. Krsti膰^a ; ^{nkrstic@chem.bg.ac.rs} ; Mira S. Bjelakovi膰^a ; ^{mbjelak@chem.bg.ac.rs} ; Vladimir D. Pavlovi膰^b ; ^{pavlovic@chem.bg.ac.rs} ; Koen Robeyns^c ; ^{koen.robeyns@uclouvain.be} ; Zorica D. Jurani膰^d ; ^{juranicz@ncrc.ac.rs} ; Ivana Mati膰^d ; ^{ivanamatic@sbb.rs} ; Irena Novakovi膰^a ; ^{irenan2003@yahoo.com} ; Du&scaron ; an M. Sladi膰^b ; ^{dsladic@chem.bg.ac.rs}
• 关键词：Phosphorus heterocycle ; 17伪-Hydroxyprogesterone ; Lawesson&rsquo ; s reagent ; X-ray analysis ; 17-Spiro-androstene derivatives ; Biological activity
• 刊名：Steroids
• 出版年：2012
• 期刊代码：142_0039128x
• 类别：bio
• 出版时间：April, 2012
• 卷：77
• 期：5
• 页码：558-565
• 文件大小：674 K

摘要

The reactions of 17伪-hydroxyprogesterone with Lawesson鈥檚 reagent (LR) in toluene, CH₂Cl₂ and/or CCl₄ gave, depending on the duration of the reaction, two diastereoisomeric androst-4-en-17-spiro-1,3,2-oxathiaphospholane-2-sulfide pairs 2a,b and 3a,b in approximately 7:3 ratio, differing in configuration at the phosphorus atom. A parallel analysis of heteronuclear 2D ¹H-¹³C spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY) enabled complete ¹H and ¹³C assignments of each isomer. Also, analysis of NOESY correlations provided evidence for the preferred conformation. X-ray analysis of 3a confirmed the structure and absolute configuration on phosphorus. A pathway for the formation of 1,3,2-oxathiaphospholane ring was proposed. Cytotoxic activity in vitro was tested against three tumor cell lines (human cervix carcinoma HeLa cells and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compound 3a and mixture 3a,b showed a moderate activity against HeLa and MDA-MB-453 cell lines while against MDA-MB-361 cell line all tested compounds exerted very weak cytotoxic effect. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, toxicity to brine shrimp Artemia salina, were evaluated. All tested compounds showed strong antifungal activity.