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

The reactions of 17α-hydroxyprogesterone with Lawesson’s 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.

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► Simple syntheses of the new androst-4-en-17-spiro-1,3,2-oxathiaphospholanes.
► The structures and absolute configurations were determined by IR, NMR and MS.
► X-ray of 3a confirmed the structure and absolute configuration on the phosphorus.
► The antimicrobial and cytotoxic activities of the compounds were tested.
► All tested compounds showed strong antifungal activity.