Natalija M. Krstić

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 Lawessons reagent (LR) in toluene, CH(2)Cl(2) and/or CCl(4) 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 (1)H-(13)C spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY) enabled complete (1)H and (13)C 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.

Steroid dimers-in vitro cytotoxic and antimicrobial activities.

The in vitro cytotoxic activity of previously synthesized steroid dimers with different spacer group (sulfide, trithiolane ring or phosphorotrithioate) and the substituent at C-17 position was tested for their possible effects against following human tumor cell lines: cervical adenocarcinoma (HeLa), chronic myelogenous leukemia (K562) and two human breast cancer cell lines (MDA-MB-361 and MDA-MB-453). These compounds, applied at micromolar concentrations, exhibited cytotoxic activity of different intensity (compared with cisplatin as a control), modality and selectivity in these malignant cell lines. The best activity against all four cell cancer lines was exhibited by dimer-sulfides. All screened compounds exerted concentration-dependent cytotoxic activity against leukemia K562 cells. The compounds which exerted the most pronounced cytotoxic action exhibited notably higher cytotoxic activities against K562, HeLa and MDA-MB-453 cells in comparison to resting and PHA-stimulated PBMC, pointing to a significant selectivity in their antitumor actions. Examination of the mechanisms of cytotoxicity on leukemia K562 cells revealed pro-apoptotic action of each of the investigated compounds applied at concentrations 2IC50. The most prominent pro-apoptotic action was exhibited by dimer-sulfide of cholest-4-en-3-one. Furthermore, almost all of the tested compounds at IC50 concentrations induced G1 phase cell cycle arrest in K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina, were evaluated. There was no antibacterial activity. The best antifungal activity was exhibited against Saccharomyces cerevisiae by dimers linked with trithiolane ring, indicating a selective activity of investigated compounds.

Thionation of Some α,β-Unsaturated Steroidal Ketones

The reactions of selected α,β-unsaturated steroidal ketones with Lawesson’s reagent (LR) in CH2Cl2 and toluene under the standard reaction conditions and with a combination of phosphorus pentasulfide with hexamethyldisiloxane (P4S10/HMDO) in 1,2-dichlorobenzene (ODCB) under microwave irradiation were investigated and for this purpose several cholestane, androstane and pregnane carbonyl derivatives were chosen. Depending on the reagent and the solvent, 19 new sulfur containing compounds, including dithiones 4c and 4d, α,β-unsaturated 3-thiones 3a-e, dimer-sulfides 2a-e, 1,2,4-trithiolanes 5a-e and phosphonotrithioates 6b-e were synthesized. All newly prepared compounds were characterized by IR, 1H- and 13C-NMR spectroscopy and elemental analysis.

Synthesis, crystal structures and antimicrobial activity of square-planar chloride and isocyanate Ni(II) complexes with the condensation product of 2-(diphenylphosphino)benzaldehyde and Girard's T reagent

Square-planar isocyanate and chloride Ni(II) complexes with tridentate PNO condensation product of 2-(diphenylphosphino)benzaldehyde and Girard’s T reagent have been synthesized and their crystal structures were determined. These Ni(II) complexes with different monodentate ligands, chloride, cyanate, and thiocyanate were tested for their antimicrobial activities against pathogenic microorganisms. The ligand and Ni(II) complexes were active not only against laboratory control strains of bacteria and yeast, but also on clinical isolates of Escherichia coli and Pseudomonas aeruginosa strains resistant to most of the clinically used antibiotics. Graphical abstract

Synthesis, characterization and biological evaluation of some novel P-heterocyclic androst-4-ene derivatives

The reactions of 21-hydroxyprogesterone with Lawesson’s reagent in toluene or

An unusual ozonolysis of the Delta(8(14))-unsaturated steroids

\mathrm {{CH}_{2}{Cl}_{2}}

Synthesis, characterization and antimicrobial activity of Pd(II) and Fe(III) complexes with ethyl (2E)-2-(2-(diphenylphosphino)benzylidene)hydrazinecarboxylate

CH2Cl2 gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17