Irena Novaković

Synthesis and biological evaluation of some 17-picolyl and 17-picolinylidene androst-5-ene derivatives

Starting from dehydroepiandrosterone (1) 17-picolyl (2), 17-picolinylidene (7), 17-picolinylidene-16-one (10 and 11), and 17-picolyl-16-one (15) derivatives of androst-5-ene were synthesized in one, two, four and five steps respectively. By the Oppenauer oxidation or dehydration of 2, 7, 10, and 11 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the corresponding A and B ring modified derivatives 3, 5, 6, 8, 9, and 12-14 were obtained. The structure of 2 was unambiguously proved by the appropriate X-ray structural analysis. Compounds 3, 5, 9, 12-14 showed inhibitory activity against the enzyme aromatase. Antibacterial activity, toxicity to brine shrimp Artemia salina, antitumor activity against three tumor cell lines (human cervix carcinoma HeLa cells, human melanoma FemX cells, and human myelogenous leukemia K562 cells) and toxicity against peripheral blood mononuclear cells were evaluated. Three tested compounds, namely 11, 13, and 15, showed strong activity against all three cell lines, the IC(50) values being in the range of 4-10 microM.

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.

Synthesis, Characterization and Biological Activity Evaluation of Novel Pd(II) and Pt(II) Complexes with Heterocyclic Hydrazone Ligands

New complexes of Pt(II) with condensation derivatives of ethyl hydrazinoacetate and either 2-acetylpyridine or 2-quinolinecarboxaldehyde, and of Pd(II) with the condensation derivative of ethyl hydrazinoacetate and 2-quinolinecarboxaldehyde were synthesized and characterized by elemental analysis, IR, 1H- and 13C-NMR spectroscopy, and molar conductivity measurements. The complexes have a square planar geometry, ligands binding as bidentates in the neutral form, and the remaining two coordination sites being occupied by chloride ions. Biological activity of new complexes, and of previously synthesized Pd(II), Cd(II), Co(III) and Zn(II) complexes with this ligand type was evaluated by the brine shrimp test. All the complexes showed a moderate activity.

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

Quinoline based mono- and bis-(thio)carbohydrazones: synthesis, anticancer activity in 2D and 3D cancer and cancer stem cell models

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

Evaluation of genotoxic potential of avarol, avarone, and its methoxy and methylamino derivatives in prokaryotic and eukaryotic test models.

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