Anticancer potential of new steroidal thiazolidin-4-one derivatives. Mechanisms of cytotoxic action and effects on angiogenesis in vitro

Abstract

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 (IC values from 8.5μM to 14.9μM), eight on HeLa cells (IC values ranging from 8.9μM to 15.1μM) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC 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.

Novel 2,3‑disubstituted 1,3‑thiazolidin‑4‑one derivatives as potential antitumor agents in renal cell adenocarcinoma

“…Considering the molecular basis of RCC, the development of targeted agents should also include the inhibitory potential associated with intracellular signal transduction pathways that drive angiogenesis (36). Furthermore, a recent study demonstrated that newly identified steroidal thiazolidin-4-ones exhibited significant anti-angiogenic effects (33). Our future studies may include these novel perspectives.…”

“…In the present study, when the chemical structures of synthesized 1,3-thiazolidin-4-ones were confirmed by spectral data, their anticancer potential was evaluated in in vitro experiments. The thiazolidin-4-one moiety is a biologically proven anticancer pharmacophore and substitution in this scaffold may further enhance its activity (15)(16)30,33). It is known that substituents may be varied but the greatest significance in properties is exerted by the group attached to the carbon atom at the 2-position of the thiazolidinone heterocycle (16).…”

4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design

“…Živković et al [ 37 ] designed a series of mono- and bis-4-thiazolidinone-containing hybrids with androstene derivatives. For the synthesized hybrids, anticancer activity studies were performed on six cancer lines: HeLa (cervical adenocarcinoma), K562 (chronic myelogenous leukemia), MDA-MB-453 (breast carcinoma), MDA-MB-361 (breast adenocarcinoma), LS174 (colon adenocarcinoma), A549 (lung carcinoma), and MRC-5 (normal lung fibroblast line).…”

An Efficient Method for the Synthesis of N‐uracil‐4‐oxo‐thiazolidines without Catalyst

“…In recent years, the chemistry of 4‐thiazolidinone derivatives has been the subject of intense research by biologists and organic chemists because such compounds represent substantial scaffolds in drug discovery . According to this approach, thiazolidin‐4‐ones have been reported to own wide spectrum of biological activity such as antimicrobial , antitubercular , antitumoral , anticancer , anti‐inflammatory , antiglioma , anticonvulsant , anti‐HIV‐1 , antioxidant , and analgesic properties .…”