•The synthesis of new steroidal mono- and bis(thiazolidin-4-ones) was performed.•Pro-apoptotic action of 4a and 5a on HeLa cells.•Apoptosis in HeLa cells through extrinsic and intrinsic signaling ...pathways.•New steroidal mono- and bis(thiazolidin-4-ones) showed ability to decrease angiogenesis in vitro.
The synthesis and cytotoxic activities determination of new steroidal mono- and bis(thiazolidin-4-ones) 4a–f and 5a–f have been performed. Their anticancer action was also evaluated in comparison to previously synthesized and reported corresponding steroidal thiosemicarbazones. All compounds were obtained as stereoisomeric mixtures with different configuration (E or Z) in the hydrazone moiety at the C-3 position. After several consecutive crystallizations diastereomerically pure major (E)-isomers of mono-thiazolidin-4-ones were isolated. The structure and stereochemistry of 2,4-thiazolidinedione,2-(17-oxoandrost-4-en-3-ylidene)hydrazone were confirmed by X-ray analysis. A pathway for the formation of thiazolidin-4-one ring was proposed. The steroid thiazolidinone derivatives examined in this study exerted selective concentration-dependent cytotoxic activities on six tested malignant cell lines. Ten out of twelve examined compounds exhibited strong cytotoxic effects on K562 cells (IC50 values from 8.5μM to 14.9μM), eight on HeLa cells (IC50 values ranging from 8.9μM to 15.1μM) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC50 values from 12.7μM to 25.6μM) than cisplatin (21.5μM) which served as a positive control. Eight of these ten compounds showed high selectivity in the cytotoxic action against HeLa and K562 cancer cell lines when compared with normal human fibroblasts MRC-5 and normal human PBMC. The study of mechanisms of the anticancer activity of the two selected compounds, mono- and bis(thiazolidin-4-one) derivatives of 19-norandrost-4-ene-3,17-dione 4a and 5a, revealed that both of these compounds induced apoptosis in HeLa cells through extrinsic and intrinsic signalling pathways.
Treatment of EA.hy926 cells with sub-toxic concentrations of these compounds led to the inhibition of cell connecting and sprouting, and tube formation. The synthesized compounds exhibited poor antioxidant activity.
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.
In this work, Pt(II) complexes of previously synthesized steroidal thiosemicarbazones were synthesized and characterized. The ligands and their metal complexes were studied by analytical and ...spectroscopic data (elemental analysis, IR, 1D-NMR and 2D-NMR, HSQC, HMBC, NOESY, COSY), the analysis of which enabled complete 1H and 13C assignments of each compound including E and Z isomers. All the synthesized ligands and complexes were screened for their cytotoxic and antimicrobial activity. The results demonstrate that the new steroidal thiosemicarbazone complexes were significantly less cytotoxic than the corresponding steroidal thiosemicarbazones. In addition, complexes showed lower antimicrobial activity than the standard drugs, similar to the activity of the starting thiosemicarbazones.
A series of new steroidal mono- and bis(thiosemicarbazones) ( 2a–e and 3a–e ) and corresponding mono- and bis(1,3,4-thiadiazolines) ( 4a–e and 5a–e ) was synthesized, characterized and evaluated for ...their anticancer activity. Detailed NMR analysis of the mono- and bis(thiosemicarbazones) revealed the presence of two stereoisomers ( Z and E ) with different configurations in the hydrazone moiety at the C-3 position, where the substituents on the C(3)N double bond in the main isomers adopted the E configuration. The configurations at C-3 and C-17 in thiadiazolines 4a–e and 5a–e were deduced by detailed NMR analysis as well as by the examination of Dreiding molecular models and X-ray analysis of 3-thiadiazoline 4a , which confirmed the structure and absolute configuration at C-3. The synthesized compounds were tested against six cancer cell lines (HeLa, K562, MDA-MB-361, MDA-MB-453, LS174 and A549), the normal human cell line MRC-5 and peripheral blood mononuclear cells (PBMC) isolated from healthy donors. The best activity was exhibited by 3-thiosemicarbazones 2a , 2b , 2c and 2e and 3,17-bis(thiadiazolines) 5a and 5d . Examination of the mechanisms of cytotoxicity on cervical adenocarcinoma HeLa cells revealed the pro-apoptotic action of these compounds, which triggered both extrinsic and intrinsic apoptotic pathways. These compounds also showed the ability to decrease angiogenesis in vitro . In addition, 3,17-bis(thiadiazolines) 5a and 5d showed high selectivity in anticancer activity against all the examined malignant cell lines. Compound 5a displayed prominent anticancer potential. The tested compounds showed poor antimicrobial 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.
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.
The reactions of 21-hydroxyprogesterone with Lawesson’s reagent in toluene or
CH
2
Cl
2
gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17
β
...-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17
β
-ylidene)-1,3,2-oxathiaphospholane–2-sulfide (3), 4-(3-oxoandrost-4-en-17
β
-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17
β
-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
1
H
-
13
C
spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete
1
H
and
13
C
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.
Graphic abstract
The interactions of nine amino acid derivatives of tert-butylquinone with biomacromolecules were studied. Sodium dodecyl sulphate (SDS) gel electrophoresis and mass spectrometry confirmed the ...absence of modifications of lysozyme by any of the synthesized compounds. Spectrophotometric studies demonstrated hyperchromism, i.e., the existence of interactions between the quinones and calf thymus DNA (CT-DNA). Determination of the binding constants by absorption titration indicated weak interactions between the quinone derivatives and CT-DNA. The quenching of fluorescence of the intercalator ethidium bromide (EB) from the EB–CT-DNA system and of the minor groove binder Hoechst 33258 (H) from the H–CT-DNA system by the synthesized derivatives indicated interactions of the compounds and CT-DNA. Circular dichroism(CD) spectra demonstrated a non-intercalative binding mode of the quinone derivatives to CT-DNA. Molecular docking results confirmed binding to the minor groove. The electrophoretic pattern showed no cleavage of the pUC19 plasmid in the presence of any of the synthesized compounds. The ability of the derivatives to scavenge radicals was confirmed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) test. All the presented results suggest that the DNA minor groove binding is the principal mechanism of action of the examined amino acid derivatives.
Abstract
Hepatitis B virus (HBV) increases morbidity and mortality among people with HIV (PWH). We retrospectively analyzed HBV incidence among 5785 PWH. Fourteen had newly positive hepatitis B s ...antigen (mean 5.2 person-years of follow-up, 46.4/100 000 infections/year). These data show gaps in HBV vaccination and in the preventative efficacy of HBV-specific antiretroviral therapy.
•The synthesis of new steroidal mono- and bis(semicarbazones) was performed.•The new carbazate esters were obtained.•The structures were determined by IR, NMR, HRMS and elemental analysis.•The ...antimicrobial and cytotoxic activities of the compounds were tested.•The replacement of CS with CO in steroidal hydrazone decrease biological activity.
Eleven new steroidal mono- and bis(semicarbazones) 2a–e, 4d and 3a–e have been prepared starting from various 3-oxo-α,β-unsaturated steroids. Mono-semicarbazones 2a–e were further subjected to ethyl chloroacetate in boiling absolute ethanol but, instead of expected intramolecular cyclocondensation reaction products, the new carbazate esters 5a-e were obtained. The structures of all synthesized compounds and identification of each E/Z isomer were deduced by elemental analysis, HRMS, NMR, and IR spectroscopy. Preliminary screening for the cytotoxic activity in vitro of the new compounds has been conducted against three cancer cell lines, K562, Jurkat and HeLa cells. HeLa cells were the most sensitive while K562 cells were the least sensitive to the cytotoxic action of the novel steroid derivatives. Compounds 2e, 3c and 5e were found to have the best but still moderate cytotoxic effects. All tested compounds showed very weak antimicrobial activities. These results demonstrate that the replacement of thioxo group with carbonyl group in steroidal hydrazone derivatives resulted in decrease in their biological activity.
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