Synthesis, characterization and in vitro cytotoxic activities of new steroidal thiosemicarbazones and thiadiazolines

Abstract

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.