Discovery of tropinone-thiazole derivatives as potent caspase 3/7 activators, and noncompetitive tyrosinase inhibitors with high antiproliferative activity: Rational design, one-pot tricomponent synthesis, and lipophilicity determination.

We have designed novel tropinone-thiazole derivatives that showed high antiproliferative activity against a variety of cancer cell lines via caspase 3/7 activation mechanism. Among the derivatives, compounds 3b-3h were found to exhibit high activity against human leukemia (MV4-11), human lung carcinoma (A549), human breast carcinoma (MCF-7), and skin melanoma (B16-F10) cancer cell lines, with IC ₅₀ values of 5.43-11.06 μM. The lead compound 3g increases caspase 3/7 activity in A549 cells 25 times more than the control, and 2 times more than reference drug camptothecin. We have also found that tropinone-thiazole derivatives exhibit high tyrosinase inhibitory activity. The lead compounds 3g and 3h showed tyrosinase inhibition effect, with IC ₅₀ values 3.22 and 3.51 μM, respectively. These inhibitory activities are 22 times higher than the activity of kojic acid (IC ₅₀ 72.27 μM) and 120 times higher than activity of ascorbic acid (IC ₅₀ 386.5 μM). For compounds 3g and 3h, the experimentally determined lipophilicity correlates very well with their enzymatic activities. These data suggest that presented compounds could constitute lead anticancer drug candidates.
(Copyright © 2019 Elsevier Masson SAS. All rights reserved.)