Synthetic And Biological Activities On The Studies Of Multi-Substituted Heterocycle Compounds

Microtubules are among the most successful targets for cancer chemotherapy.They are important in many cellular processes such as the development andmaintenance of cell shape, transport of components through cells, cell signaltransduction, and cell division. Microtubule-targeted drugs can lead to mitotic blockand cell apoptosis, and some also can act as vascular-targeting agents, depolymerizingmicrotubules of newly formed vascular to shut down the blood supply to tumours.The microtubule-targeted antimitotic drugs are usually classified into three maingroups, Vinca alkaloids, paclitaxels, and colchicines domain. The Vinca alkaloids andpaclitaxels, which are first isolated from natural plants, are difficult to obtain by totalsynthesis as well as their serious side effects of neurotoxicity and myelosuppression.As a result, colchicines and its analogues have generated considerable interest due tosimple and small molecule structure. The work following has been carried out in thispaper.1.The development and SAR of microtubule-targeted agents that bind to colchicinesdomain are reviewed and three series of target compounds with differentsubstituted groups are designed.2.o-Bromophenol was alkylated by alkyl halides followed via acylation withpropionyl chloride and bromination with bromine in refluxing chloroform toafford α-bromoaromatic ketone;Multi-alkoxybenzaldehydes were treated withGrignard reagent from bromoethane, then oxidized with Jone's reagent to givearomatic ketone. Deprotonation of aromatic ketone by sodium amide in liquidammonia and consequent alkylation with α-bromoaromatic ketone produce thekey intermediates for target compounds——1,4-diaryl-2,3-dimethyl-1,4-butane-diones.3.Diketones were treated with diverse cyclization reagents under different reactionconditions to afford multi-substituted heterocyclic compounds. 1,4-Dicarbonylswere cyclized to multi-substituted furans, thiophenes, pyrroles or N-alkyl pyrrolesupon their treatment with hydrochloric acid/methanol solution in dichloromethane,Lawesson reagent, ammonium acetate or alkyl amine/acetic acid, respectively.Thirty-nine target heterocycles were obtained and thirty-seven of them are newcompounds. The target compounds were confirmed by 1HNMR and 13CNMR.4.Multi-substituted heterocyclic compounds were converted to correspondingamine-containing target compounds with diverse substituted amines via thepalladium-catalyzed coupling reaction under the catalyst of PdCl2(dppf), theligand of DPPF, and the base of t-BuONa. Amines, including alkyl amines(methylamine, n-propylamine, n-butylamine, and benzylamine), secondary amines(N,N-diethylamine, pyrroline, piperidine, and morpholine), aromatic amines(aniline, 4-methylaniline, 4-methoxyaniline, and 4-chloroaniline), andEDG-anilines (2-methoxyaniline, 4-ethoxyaniline, 3,4-dimethoxy aniline,3,4,5-trimethoxyaniline, and 4-benzyloxyaniline), were reacted withbromine-containing heterocycle compounds to give thirty-eight novelamine-containing heterocycle compounds, which were confirmed by 1HNMR and13CNMR. The compound 112 was also identified by X-ray crystallography.5.Some of target compounds were evaluated their anticancer and antiviral activitiesin vitro. Several heterocycle compounds showed good and potent inhibition toMCF-7 and one of them was found to be almost identical activity to paclitaxel.Several compounds were found possessing certain anti-HIV-1 efficacy as well aslow cytotoxciities.