الفهرس 
Introduction
Vinblastine analogousOnly 14 pages are availabe for public view
 |  | from | 180 |  |  |
| | | from | 180 | | |
Abstract
Many of the currently available antitumor drugs are incapable of differentiating between normal and neoplastic cells and also are unable to beat primary or secondary resistance mechanisms evolved within the tumor cells in the process of cell division. Thus, there is a persistent need for novel antitumor agents with great potency and fewer toxicity in non-cancerous cells, and be able to act on unique biological targets. Tubulin has become a significant target in cancer chemotherapy. This heterodimeric protein plays a principal role in the mitotic spindle development. Tubulin inhibitors are considered an important category in cancer chemotherapy. Most tubulin inhibitors which attach to the paclitaxel and vinblastine binding sites are greatly potent but their clinical use is restricted due to higher toxicity and resistance. Tubulin inhibitors that bind to the colchicine binding site can mainly overcome the above mentioned drawbacks and have therapeutic advantages over vinca alkaloids and taxanes. Among the existing well-known antitumor agents, chalcones are considered as an essential class of small appropriate molecules in cancer chemotherapy. Chalcones are composed of a three-carbon α, β-unsaturated carbonyl system, the presence of α, β-unsaturated carbonyl system in chalcone gives it a variety of biologically activities including cytotoxic activity. Examples of chalcone based tubulin polymerization inhibitors are Colchicine and Combretastatin A4 Analogous. In this study, a series of twenty chalcone derivatives 3a-l, 5a-e, 7 and 10a-b with Substitution/ addition of halogens, methoxy group and tri-methoxyphenyl (TMP) on both rings (A and B) were designed then synthesized via the Claisen-Schmidt condensation reactions and characterized by elemental analysis (% C, H, N) and the spectroscopic data (1H-NMR and 13C-NMR). The cytotoxic activities were evaluated against both breast MCF7 and liver HepG2 cancer cell lines as well as breast Hs371.T and liver AML12 normal cell lines. Out of our candidates, there were five compounds 3b, 3d, 3h, 7 and 10b that showed a broad superlative antitumor activity against both MCF7 and HepG2 cell lines. Surprisingly, 3h revealed the most potent inhibitory activity (GI50 =5.43 ± 0.170 μM for MCF7 and GI50 =1.80 ± 0.50 μM for HepG2) and exhibited the most effective inhibitory activity of tubulin with IC50 = 4.51± 0.13 μM. 3h and 3k exerted high selectivity toward cancer cell compared to normal human, Hs371.T and AML12, cell lines. 3h and 3k exhibited cell cycle arrest at G2/M and induced apoptosis compared to control cells. Molecular docking of all synthesized compounds was performed to insert compounds into the crystal structure of tubulin at colchicine binding site and to determine the best binding mode. Generally, the result of the molecular docking study imparted that 3h was a potential tubulin inhibitor.