Design,Synthesis And Anti-cancer Activity Of Combretastatin Analogues

Tubulin is a 110-kDa heterodimeric protein composed of two subunits α-and β-(-450 amino acids each)and it is the basic subunit of MT.Microtubule is one of the key components of the cytoskeleton and plays an important role in the maintenance of the cell shape and the process of signal transduction and mitosis.Due to the extreme importance of microtubule in the process of mitosis,tubulin becomes one of the most important targets for development of new anticancer drugs and tubulin inhibitors are used for the treatment of cancer nowadays.These inhibitors have antitumor activity by inhibiting or promoting the assembly of tubulin microtubules and interfering the process of cell mitosis.As for the localization of their binding sites,most of drugs bind to one of three sites on different parts of the protein:the colchicines,vinblastine and taxol sites.Most MT-stabilizing agents bind at the PTX-binding site on(3-tubulin,including the taxanes,epothilones,eleutherobin and discodermolide.Known MT-destabilizing agents bind either to the colchicines or to the vinblalstine binding sites.Microtubule destabilizing compounds act by inhibiting microtubule polymerization and include several agents,such as colchicines,combretastatinA-4,podophyllotoxin,vinca alkaloids and a number of structurally unrelated small molecules.Combretastatin A-4(CA-4)is a natural product isolated by Pettit and coworkers from the bark of the South African bush willow tree Combretum caffrum in 1982.It is the most potent compound in combretastatins family,as well as one of the most potent inhibitors of colchicines site.CA-4 is not a substrate of the multi-drug resistance(MDR)pump,and exhibits superior activity against MDR positive cancer cell lines.Moreover,it also has been reported to have angiogenesis inhibition which interferes the process essential for tumor growth.For its simple structure and high activity,CA-4 becomes the most representative ligand of the colchicines site and is important in the design of structural diverse colchicines binding site inhibitors.The olefinic component of CA-4 has undergone major molecular changes.Among the main reasons for this is the observation that the presence of a double bond in a Z configuration is fundamental to having high cytotoxic and antitubulin action,while the E analogue is significantly less potent.It is believed that the olefinic bond plays a more constitutive role than a binding role during the biological interaction;it allows placement of the benzene rings at an appropriate distance and gives the molecule the right dihedral angle to maximize the interaction with the target.The Z stilbenic double bonds can easily isomerize under the influence of heat,light,and protic media.Therefore,a number of groups have attempted to modify the olefinic bridge to stabilize the conformation to attempt to increase the biological effects of the compound or to minimize the possible metabolism that the olefinic group might undergo.Objective:To design,synthesis and anti-cancer activity evaluation of combretastatin anloguesMethods:Combrestastatin analogues can be synthesized by starting material 2-bromo-phenylacetic acid(2)by the catalytic reaction of methanol and concentrated sulfuric acid to give 2-bromo-phenylacetate(3),3 reacting with the compound 4-chloro-phenol(4)under alkaline conditions in dioxane as a solvent and heating conditions obtained 2-(2-(4-chlorophenooxy))phenylacetate(5),5 hydrolyzed with sodium hydroxide to give 2-(2-(4-chlorophenoxy))phenylacetic acid(6).6 reacting with thionyl chloride in dichloromethane as solvent obtained the compound 2-(2-(4-chlorophenoxy))phenylacetyl chloride(7).7 catalyzed by aluminum chloride cyclization obtained compound 8-chloro-dibenzo[b,f]oxa Tropylium cation-10(11H)-one(8).8 reduced with sodium borohydride obtained the compound 8-chloro-10,11-dihydro-dibenzo[b,f]Tropylium cation-oxa-10-ol(9),9 reacting with thionyl chloride obtained compound 11-dichloro-10,11-dihydro-dibenzo[b,f]oxa Tropylium cation(10),10 dechlorination reaction with DBU obtained the title compound 2-chloro-dibenzo[b,f]oxa Tropylium cation(1).The structure of intermediates and target products was confirmed by mass spectrum,nuclear magnetic.Results:Successfully synthesized eight new target Combrestastatin analogues,also investigated the cell activity of these compounds.Conclusion:Successfully synthesized eight new target compounds,moiety of these compounds displayed a certain anti-cancer activity.