DESIGN,SYNTHESIS AND CHARACTERIZATION OF NOVEL SERIES OF 1,3-THIAZOLE CONTAINING HETEROCYCLES AS INHIBITORS OF DHFR FOR USE AS ANTICANCER AGENTS

摘要

Dihydrofolate reductase(DHFR)is an indispensable cellular enzyme which catalyzes the reduction of 7,8-dihydrofolate to tetrahydrofolate(THF)[1].Tetrahydrofolate is used as a cofactor during the formation of serine and thymidine(required for DNA replication)via a one carbon transfer reaction pathway involving pyrimidine,purine,and amino acid biosynthesis,resulting in cell growth and proliferation.It is also used in the methylation of dUMP to dTMP [2].DHFR is a highly targeted,pivotal enzyme in human therapy as it is the only source of tetrahydrofolate [3].DHFR inhibitors are potential pharmacological agents showing promising results as novel anti-cancer,anti-bacterial,antimalarial therapeutics.Methotrexate is a popular DHFR inhibitor whose biological potency is offered by 1,3-thiazole,which exists in many fused heterocyclic systems.Several compounds bearing thiazole heterocycle such as tiazofurin,4-phenyl-thiazole-1,3,5-triazines,netropsin and thia-netropsin were reported as nonclassical DHFR inhibitors [4].Molecular modelling studies have concluded that recognition with key amino acid Leu4,Glu30,Arg22 and Val115 are essential for DHFR binding and the thiourea moiety is seen as an anchoring group to enhance the DHFR inhibition [5].In view of these facts,the present study targeted the design,synthesis and biological evaluation of novel series of 1,3-thiazole heterocycles containing electron withdrawing groups acting at the DHFR enzyme active site.The obtained model could be useful for the development of a new class of DHFR inhibitors.