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

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 th...

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Bibliographic Details
Published in:RSC advances 2016-01, Vol.6 (41), p.34312-34333
Main Authors: Zivkovic, Marijana B, Matic, Ivana Z, Rodic, Marko V, Novakovic, Irena T, Sladic, Dusan M, Krstic, Natalija M
Format: Article
Language:English
Subjects:
Anticancer properties
Biotechnology
Hydrazones
In vitro testing
Military aircraft
Military planes
Molecular structure
Nuclear magnetic resonance
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Summary: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.
ISSN:2046-2069
2046-2069
DOI:10.1039/C6RA01516F