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

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 IC 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 (IC= 20 ± 0.51 μM), whilst their IC 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.