New 1,3,4-thiadiazoles as potential anticancer agents: pro-apoptotic, cell cycle arrest, molecular modelling, and ADMET profile.

Autor: Hekal MH; Department of Chemistry, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt., Farag PS; Department of Chemistry, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt., Hemdan MM; Department of Chemistry, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt., El-Sayed AA; Department of Chemistry, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt., Hassaballah AI; Department of Chemistry, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt., El-Sayed WM; Department of Zoology, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt waelelhalawany@hotmail.com wael_farag@sci.asu.edu.eg +202 2684 2123 +202 2482 1633.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2023 May 25; Vol. 13 (23), pp. 15810-15825. Date of Electronic Publication: 2023 May 25 (Print Publication: 2023).
DOI: 10.1039/d3ra02716c
Abstrakt: A series of novel 1,3,4-thiadiazoles was synthesized via the reaction of N -(5-(2-cyanoacetamido)-1,3,4-thiadiazol-2-yl)benzamide (3) with different carbon electrophiles and evaluated as potential anticancer agents. The chemical structures of these derivatives were fully elucidated using various spectral and elemental analyses. Out of 24 new thiadiazoles, derivatives 4, 6b, 7a, 7d, and 19 have significant antiproliferative activity. However, derivatives 4, 7a, and 7d were toxic to the normal fibroblasts, and therefore were excluded from further investigations. Derivatives 6b and 19 with IC 50 at less than 10 μM and with high selectivity were selected for further studies in breast cells (MCF-7). Derivative 19 arrested the breast cells at G2/M probably through inhibition of CDK1, while 6b significantly increased the sub-G1 percent of cells probably through induction of necrosis. These results were confirmed by the annexin V-PI assay where 6b did not induce apoptosis and increased the necrotic cells to 12.5%, and compound 19 significantly increased the early apoptosis to 15% and increased the necrotic cells to 15%. Molecular docking showed that compound 19 was like FB8, an inhibitor of CDK1, in binding the CDK1 pocket. Therefore, compound 19 could be a potential CDK1 inhibitor. Derivatives 6b and 19 did not violate Lipinski's rule of five. In silico studies showed that these derivatives have a low blood-brain barrier penetration capability and high intestinal absorption. Taken together, derivatives 6b and 19 could serve as potential anticancer agents and merit further investigations.
Competing Interests: Authors declare that they have no conflict of interest.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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