الفهرس 
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Abstract
A wide variety of 1,2,3-triazole derivatives was reported in literature as potential anticancer agents. In the present study, thirty-two compounds of new 1,2,3-triazole derivatives bearing cytotoxic moieties as quinoline, oxadiazole, thiazole, thiazole-Schiff base or chalcone have been synthesized via four schemes. Reaction times were monitored using TLC plates, and the structures of the target compounds were confirmed based on spectra analysis including IR, 1H-NMR, 13C-NMR and mass spectroscopy. All synthesized compounds were examined in vitro at the National Cancer Institute (NCI), USA, at a single-dose concentration of 10 µM against a panel of 60 cell lines taken from nine different tissues including blood, lung, colon, CNS, skin, ovary, kidney, prostate and breast. The results revealed that leukemia cell lines were the most sensitive cell lines, and five derivatives with chalcone moiety were the most potent. MTT assay was performed for chalcone hybrids 96b, d, f, h, i against the most sensitive cancer cell lines and their corresponding normal cell lines. The results revealed strong potency reached to nanomolar range of IC50 values, in addition to high selectivity towards cancer cells rather than normal cells. The Physico-chemical properties of the potent derivatives 96d, f were predicted using Molinspiration software. It was observed that they well comply the Lipinski’s rule of five and Veber’s criteria which indicated the drug-likeness properties of these compounds. Mechanistic evaluation of the most potent compound 96d in RPMI-8226 cell line was studied through measuring its effect on HDACs, NF-kB, EGFR, VEGFR, topoisomerase-2, tubulin, Bax, Bcl-2, caspases-3, -7, -9 and PARP-1. Compound 96d causes cell cycle arrest at G2/M phase and induced apoptosis in a dose dependant manner via triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 3, 7 and 9. The current study evidently identified the potential of compound 96d to be one of the promising lead for future development of active anticancer agents, and potentialy offer new insights in treating multiple myeloma RPMI-8226.