Design, Synthesis and Biological Evaluation of a Novel Series of Thiadiazole- Based Anticancer Agents as Potent Angiogenesis Inhibitors

Abstract

Background: Thiadiazole has attracted a great deal of interest as a versatile heterocycle for the discovery and development of potent anticancer agents. Thiadiazole derivatives exert potent antitumor activity against a variety of human cancer cell lines through various mechanisms.

Objective: The goal of this work was to design and synthesize thiadiazole-based anticancer agents with anti-angiogenic activity.

Methods: N-aryl-2-[(5-(aryl)amino-1,3,4-thiadiazol-2-yl)thio]acetamides (4a-r) were synthesized via the reaction of 5-(aryl)amino-1,3,4-thiadiazole-2(3H)-thiones with N-(aryl)-2-chloroacetamides in the presence of potassium carbonate. The compounds were investigated for their cytotoxic effects on three cancer (A549, HepG2, SH-SY5Y), two normal (HUVEC and 3T3-L1) cell lines using MTT and WST-1 assays. In order to examine whether the compounds have anti-angiogenic effects or not, HUVECs were cultured on matrigel matrix to create a vascular-like tube formation.

Results: Compounds 4d, 4m and 4n were more effective on A549 human lung adenocarcinoma cells than cisplatin. The IC₅₀ values of compounds 4d, 4m and 4n for A549 cell line were found to be 7.82 ± 0.4, 12.5 ± 0.22, 10.1 ± 0.52 μM, respectively when compared with cisplatin (IC₅₀= 20 ± 0.51 μM), whilst their IC₅₀ values for HUVEC cell line were determined as 138.7 ± 0.84, 78 ± 0.44, 177.6 ± 0.2 μM, respectively after 48 h of the treatment. The concentrations (10-20-50 μM) of compounds 4d, 4e, 4l, 4m, 4n, 4q and 4r were found to inhibit vascular like tube formation.

Conclusion: According to their anticancer and anti-angiogenic effects, compounds 4d, 4m and 4n may be potential anticancer agents for further in vivo studies.

Keywords: Benzothiazole; MTT; WST-1.; angiogenesis; anticancer activity; thiadiazole; thiazole.