Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones

Mehmood, Hasnain; Musa, Mustapha; Woodward, Simon; Hossan, Md Shahadat; Bradshaw, Tracey D.; Haroon, Muhammad; Nortcliffe, Andrew; Akhtar, Tashfeen

Abstract

Cyclization of substituted thiosemicarbazones with α-bromo-4-cyanoacetophenone allows rapid single-step sustainable syntheses of 4-cyanophenyl-2-hydrazinylthiazoles libraries (30 examples, 66–79%). All show anticancer efficacy against HCT-116 and MCF-7 carcinoma cell lines with the majority being more active than cisplatin positive controls. The compounds 2-(2-(2-hydroxy-3-methylbenzylidene) hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-((pentafluorophenyl)methylene)-hydrazinyl)-4-(4-cyanophenyl) thiazole (3a′) show optimal GI50 values (1.0 ± 0.1 μM and 1.7 ± 0.3 μM) against MCF-7 breast cancer cells. Against colorectal carcinoma HCT-116 cells, (2-(2-(3-bromothiophen-2yl)methylene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3b′), 2-(2-(2-hydroxy-3-methylbenzylidene) hydrazinyl)-4-(4-cyanophenyl)thiazole (3f), 2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4-(4-cyanophenyl)thiazole (3f) and 2-(2-(1-(4-fluorophenyl)ethylidene)hydrazinyl)-4-(4-cyanophenyl) thiazole (3w) are the most active (GI50 values: 1.6 ± 0.2, 1.6 ± 0.1, 1.1 ± 0.5 and 1.5 ± 0.8 μM respectively). Control studies with MRC-5 cells indicate appreciable selectivity towards the cancer cells targeted. Significant (p < 0.005) growth inhibition and cytotoxicity effects for the thiazoles 3 were corroborated by cell count and clonogenic assays using the same cancer cell lines at 5 and 10 μM agent concentrations. Cell cycle, caspase activation and Western blot assays demonstrated that compounds 3b′ and 3f induce cancer cell death via caspase-dependent apoptosis. The combination of straight forward synthesis and high activity makes the thiazoles 3 an interesting lead for further development.

Citation

Mehmood, H., Musa, M., Woodward, S., Hossan, M. S., Bradshaw, T. D., Haroon, M., …Akhtar, T. (2022). Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones. RSC Advances, 12(52), 34126-34141. https://doi.org/10.1039/d2ra03226k

• Journal Article Type: Article
• Acceptance Date: Nov 18, 2022
• Online Publication Date: Nov 28, 2022
• Publication Date: Nov 28, 2022
• Deposit Date: Dec 20, 2022
• Publicly Available Date: Dec 20, 2022
• Journal: RSC Advances
• Print ISSN: 2046-2069
• Electronic ISSN: 2046-2069
• Publisher: Royal Society of Chemistry (RSC)
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 52
• Pages: 34126-34141
• DOI: https://doi.org/10.1039/d2ra03226k
• Keywords: General Chemical Engineering; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/14322403
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2022/ra/d2ra03226k