Synthetic Modification Of R-(+)-XK469 And Design,Synthesis,Preliminary Biological Evaluation Of Novel Histone Methyltransferase Inhibitors

PART I:SYNTHETIC RESEARCH OF R-(+)-XK469As an important class of nitrogen-containing heterocyclic chemotype,quinoxaline has been widely used in chemistry,biology,medicine,and other research fields.Quinoxaline derivatives are reported to possess a broad spectrum of biological activities,including but not limited to anti-tumor,anti-HIV,anti-bacterial,anti-tuberculosis.Moreover,they also have excellent inhibitory potencies against some pathogenic microorganisms.(R)-2-(4-((7-chloroquinoxalin-2-yl)oxy)phenoxy)propanoic acid,abbreviated as R-(+)-XK469,is a synthetic quinoxaline oxybenzene derivatives of propionic acid.It was developed by DuPont Pharmaceuticals Inc as a catalytic inhibitor of DNA topoisomerase ?? with significant anti-tumor efficacies towards a variety of tumor cell lines.It has currently entered phase I trial for the treatment of various solid and hematologic tumors as a potent candidate,with a code NSC 698215.Even more,it can significantly inhibit many drug-resistant or even multidrug resistant tumor cells.Among the two optical isomers of XK469,although both of the R-(+)and R-(-)isomers have anti-tumor activities,R-(+)-isomer has higher antitumoral potency and lowered cytotoxicity than that of the R-(-)-isomer,making the R-(+)--isomer is more anticipated.Enlightened by the significant prospects of R-(+)-XK469,we expected to develop a more efficient and eco-friendly synthetic protocol.To this end,we initially analyzed the available synthetic approaches and proposed some modifications,which are summarized as follows:?)Activation of amino group rather than utilization the original carboxymethylation reaction to enhance the yield of key intermediate 1;?)As far as the optimizations on the branch chain are concerned,esterification of(S)-2-bromopropionic acid methyl ester instead of L-lactic acid methyl ester with para-diphenol was conducted to reduce the synthetic steps and increase yield;?)Finally,the influences of base,solvent,reactant proportion,temperature,charging sequence were investigated and optimized accordingly.All in all,we have obtained the target compound R-(+)-XK469 with a total yield of 24.6%,which is higher than that of the reported methods,with a relatively satisfactory purity of 98.8%.PARTII:DESIGN,SYNTHESIS AND PRELIMINARY BIOLOGICAL EVALUATION OF HISTONE METHYLTRANSFERASE INHIBITORS(HMTIS)Recently,although great achievements have made on the development of anti-HIV chemotherapies,e.g.highly active antiretroviral therapy(HARRT),which can greatly decrease viral load in HIV patients,AIDS is still not entirely cure and the quest for an effective AIDS cure still continues.The AIDS virus is difficult to be entirely eliminated,largely due to the fact that a large amount of virus is hidden in latent viral reservoir.As a result,most of anti-HIV medication is actually lost upon them,which has been the main obstacle to the effective eradication of HIV virus infection.Histone methyltransferase(HMT),which contains the classical SET domain,is one of the major methyltransferases of euchromatin.Evidences have showed that over-expression of HMT is highly associated with the silence of the virus,and thereby inhibition of the abnormal activity of HMT can prevent viral gene silencing.Once the virus is activated,the anti-HIV chemotherapies,e.g.HAART,will be effective to the elimination of HIV virus.To this end,a series of novel quinoxaline derivatives were designed as histone methyltransferase inhibitors(HMTIs)based on the structural characteristics of reported HMTIs and computer-aided drug design.The preliminary bioactivity evaluation showed that the newly designed compounds had slightly higher activity than the negative control,but gave much lower potencies than the positive control prostratin.The reasons for the poor activity are largely to the following factors:?)The lack of a branched group at 7-position which corresponds to alkoxy group of the UNC series made the newly designed compounds failed to efficiently occupy,the pocket ? of target protein,which is especially important for achieving potent activity;?)The volume of nitrogen-containing aliphatic chain(R2)is small,while 6-or 7-membered with larger volume is more desirable to introduce so as to generate well occupation with pocket ? of target protein;?)The nitrogen-containing aliphatic ring rather than biphenyl moiety is more suitable to introduce in order to increase polarity and bring improved bioavailability of the compound.Based on these reasons,more effort is needed on further structural modifications to obtain improved activity.