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Expanding the Alkaline Phosphatase Inhibition, Cytotoxic and Proapoptotic Profile of Biscoumarin‐Iminothiazole and Coumarin‐Triazolothiadiazine Conjugates
Author(s) -
Iqbal Jamshed,
Ejaz Syeda Abida,
Ibrar Aliya,
Umar Muhammad Ihtisham,
Lecka Joanna,
Sévigny Jean,
Saeed Aamer
Publication year - 2018
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201801863
Subject(s) - coumarin , alkaline phosphatase , cytotoxicity , chemistry , apoptosis , cytotoxic t cell , stereochemistry , inhibitory postsynaptic potential , enzyme , pharmacology , biochemistry , in vitro , biology , endocrinology , organic chemistry
The present study was aimed to explore the inhibitory potential of coumarin‐hybrids bis‐coumarin‐iminothiazoles (5a‐k) and coumarin‐triazolothiadiazines (10a‐j) against both tissue‐nonspecific alkaline phosphatase ( h ‐TNAP) and intestinal alkaline phosphatase ( h ‐IAP) and to link their AP inhibitory potential with possible anti‐proliferative and pro‐apoptotic effect. All investigated compounds were potent inhibitors of h ‐TNAP and h ‐IAP with several fold better inhibition as compared to standard drugs. In bis‐coumarin‐iminothiazole series, 5f (IC 50 =0.35±0.01 μM) was found as a lead candidate against h ‐TNAP demonstrating a ∼55‐fold higher inhibitory potential as compared to levamisole, whereas, among coumarin‐triazolothiadiazines, 10a (IC 50 =0.31±0.98 μM) showed ∼62‐fold inhibitory potential. Similarly, compounds 5g and 10d were most potent inhibitors of h ‐IAP with an IC 50 value of 0.22±0.87 and 0.56±0.04 μM, respectively. The detailed kinetic studies were conducted to probe the mechanism of inhibition. The four potent AP inhibitors 5f, 5h, 10a and 10g also showed maximum anti‐proliferative effect in cancer cells and apoptosis via G 2 /M phase arrest. 10a and 5f showed maximum cytotoxicity in K‐562 cells (89 and 80%, respectively) with IC 50 values of about 2.37 and 7.81 μM, respectively. Our findings suggest these derivatives as potential anti‐cancer candidates with profound anti‐proliferative and pro‐apoptotic behavior along with the ability to block purinergic signaling.