Design, Synthesis And SAR Study Of Analogues Of Combretastatin A-4 As Anti-tumor Agents

Cancer is a significant health concern in the modem world,and the second leading cause of death after cardiovascular disease in our country.Despite the development of new strategies of aggressive surgical and adjuvant therapy,little progress has been made in the successful management of advanced diseases.In recent years,there has been a growing interest in the search for anti-tumor drugs with high efficacy,low toxicity and minimum side effects.The natural products Combretastatins are one kind of perspective anti-tumor drugs. Among them,Combretastatin A-4(CA-4)strongly inhibited the polymerization of tubulin by binding to the chochicine site and showed the most potent cytotoxicity against a variety of human cancer cell lines including multiple drug-resistant cancer cell lines.Because of its structural simplicity and potent cytotoxicity,CA-4 is very attractive lead compound.Its derivative AC-7739,AVE-8082 and phosphate prodrugs CA-4P,CA-1P had been in clinic research.Especially,CA-4P is currently in phaseâ…¢clinical trials as tumor vascular targeting agent.On the basis of their SAR studies,we retained the important 3,4,5-trimethoxyphenyl pharmacophore and replaced its olefinic bond with non-heterocyclic bridge or hererocyclic bridge according to the principal of bioisosterism.In addition,we replaced ring B with substituted phenyl rings or heterocyclic rings.Therefore,a series of indolobenzamides, diaryl 3-oxo-propanenitrils,triarylureas,diarylimidazol-2-ones,diarylisoxazoles, diarylpyzoles and arylpyrimidazol-2-ones were designed,synthesized and tested for their cytotoxicities against several tumor cell lines in vitro.The results showed that indolobenzamide,diaryl 3-oxo-propanenitril and triarylurea derivatives only exhibited high inhibitory activities against HL-60 cells and/or K562 cells;most of diarylimidazol-2-one, diarylisoxazole,diarylpyzole and arylpyrimidazol-2-one derivatives exerted high cytotoxicities against all of the tested tumor cell lines.In order to gain further insight into the mechanisms of action of these compounds,the potent cytotoxic and representative compounds were assayed for their effect on cell cycle. The results showed that 141,173,191 and 195 acted as antimitotics arrested on the G2/M phase of cell cycle,which is consistent with the action of CA-4,except for 216.In addition, cell-cycle distribution analysis showed that these compounds induced cell apoptosis.The results indicated that apoptosis pathway did contribution to the antitumor activity.Furthermore,the most cytotoxic compound 141 was chosen to investigate its growth inhibitory activity on murine S-180 and murine H-22 tumor bearing models in vivo.The results indicated that 141 showed significant anticancer activity in two murine tumor bearing models.Therefore,141 is promising for further studies because of its excellent effect and relatively low toxicity.Other mechanisms of action were in further investigation.