title: Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives.
abstract: The reactions of 21-hydroxyprogesterone with Lawesson's reagent in toluene or [Formula: see text] gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D [Formula: see text]-[Formula: see text] spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete [Formula: see text] and [Formula: see text] assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.
authors.affiliation: Center for Chemistry, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Studentski trg 12-16, P. O. Box 473, 11001 , Belgrade, Republic of Serbia. nkrstic@chem.bg.ac.rs
authors.forename: Natalija M
authors.initials: NM
authors.lastname: Krstić
authors.forename: Vladimir D
authors.initials: VD
authors.lastname: Pavlović
authors.forename: Irena T
authors.initials: IT
authors.lastname: Novaković
authors.forename: Ivana Z
authors.initials: IZ
authors.lastname: Matić
authors.forename: Dušan M
authors.initials: DM
authors.lastname: Sladić
mesh_terms: D000736:Androstenes / Q000138:chemical synthesis / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003900:Desoxycorticosterone / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D005260:Female; D005658:Fungi / Q000187:drug effects; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008826:Microbial Sensitivity Tests; D009946:Organothiophosphorus Compounds / Q000737:chemistry
chemical_list: D000736:Androstenes; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D009946:Organothiophosphorus Compounds; D003900:Desoxycorticosterone; C029887:2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide