Synthesis,Biological Evaluation And 3D-QSAR Studies Of Novel 5-phenyl-1H-pyrazol Cinnamamide Derivatives As Novel Antitubulin Agents

Microtubules are major cytoskeletal protein polymers in all eukaryotic cells and involved in numerous cellular functions including chromosome segregation,intracellular transport,cell motility,and cell shape.Microtubules assemble and disassemble by a reversible process involving discrete ?/? tubulin heterodimers.This dynamic instability feature along with treadmilling gives microtubules significant role in mitosis and cell division.During cell mitosis,microtubules mediate the timely and correct attachment of chromosomes at their kinetochores to the spindle,the complex movements of the chromosomes that bring them to their properly aligned positions and the synchronous separation of the chromosomes.Given the importance of microtubules in cell mitosis,microtubules or tubulins serve as effected molecular targets for cancer chemotherapeutic agents.There are two classes of these chemotherapeutic agents,microtubule stabilizers(e.g.,paclitaxel and docetaxel),and microtubule destabilizers(e.g.,vinblastine and vincristine).Both types interfere with the mitotic spindle assembly during cell division and block cell cycle in G2/M phases,resulting in cell death.Colchicine is the first identified antimitotic drug that inhibits microtubule polymerization by binding to tubulin,and its binding site has been well characterized.Several other new compounds such as E7010,HMN-214,and CA-4 have also attracted much interest as antitubulin agents.They bound tubulins through colchicine binding site.Pyrazole and their derivatives have attracted constant interest over the past decades because of their wide range of pharmacological activities,such as antitumor,anti-inflammatory,antibacterial,analgesic,fungistatic,and anti-hyperglycemic.Besides,Pyrazole-based heterocycles play a crucial role in the arena of rigidified combretastatin analogs.Lee and co-workers described a series of 3,5-diarylpyrazoles that display low cytotoxicity in tumor cell lines due to their planar conformation.Meanwhile,chalcone and cinnamon amide share similar part of the active structure.Cinnamic acids are abundant in various natural resources and its natural analogs are unique as anticancer agents.A lot of cinnamido compounds were also synthesized and their anticancer abilities were evaluated by our research groupsThese previous researches encouraged us to integrate cinnamon amide with pyrazoles to screen compounds which have potent anticancer activities.Herein we report the synthesis and bioactivities of a series of 5-phenyl-1H-pyrazol derivatives containing cinnamoyl moiety,which were characterized by 1H NMR,13C-NMR,MS analysis.The in vitro anticancer activities of these compounds were evaluated against three cancer cell lines(MCF-7,A549 and B16-F10)by the MTT method.Among all the designed compounds,compound 5j exhibited more potent in vitro anticancer activities targeting MCF-7(IC50=0.35?M)comparing with colchicine(IC50 0.39 ?M).Subsequent anti-microtubule drug testing and cell cycle experiment verified the MTT results.In addition,to guide further researches,SAR(structure-activity relationship)was studied by QSAR model which was created based on the result of above-mentioned biological assay.