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

Zivkovic Marijana B; Matic Ivana Z; Rodic Marko V; Novakovic Irena T; Krivokuca Ana M; Sladic Dusan M; Krstic Natalija M

doi:10.1016/j.jsbmb.2017.07.031

Published July 19, 2017 | Version v.1

Journal article Open

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

1. Center for Chemistry, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Studentski trg 12-16, P. O. Box 473, 11001 Belgrade, Serbia;
2. Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
3. Faculty of Sciences, University of Novi Sad, Trg D. Obradovića 3, 21000 Novi Sad, Serbia
4. Center for Chemistry, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Studentski trg 12-16, P. O. Box 473, 11001 Belgrade, Serbia
5. Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, P. O. Box 158, 11001 Belgrade, Serbia
6. Institute for Oncology and Radiology of Serbia

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 8.5 μM to 14.9 μM), eight on HeLa cells (IC₅₀ values ranging from 8.9 μM to 15.1 μM) while against MDA-MB-361 cells six compouds exerted similar or even higher cytotoxic action (IC₅₀ values from 12.7 μM to 25.6 μM) than cisplatin (21.5 μM) 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.

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