設計與合成第六亞型組蛋白去乙醯酶抑制劑作為抗多形性膠質母細胞瘤之潛能藥物

Abstract

The aim of this thesis is to develop quinazolinone derivatives as selective HDAC6 inhibitors for the potential treatment of glioblastoma. In our previous study, a series of quinazolinone derivatives as HDAC6 inhibitors had been designed and synthesized which employed quinazolinone as core structure to serve as enzyme surface recognition group and connected with hydroxamic acid through benzyl linker. In this thesis, compound 1 was selected as a lead which displayed HDAC6 IC50 at 5 nM, 650-fold selectivity to HDAC6 versus HDAC1, and IC50 at 0.87 μM against brain cancer cell line. More modifications on quinazolin-2,4-dione and different length of linkers at 2-position were accomplished to improve the HDAC6 inhibitory activity and cytotoxicity. Furthermore, structural mimics of the tricyclic ring of Tubastatin A were also synthesized to explore the tolerance of rim region. From the results obtained from enzyme assay and cytotoxic assay, compound 5h with fluoride at ortho position of phenyl ring displayed enhanced IC50 at 0.15μM against brain cancer cell line. Removing phenyl ring at N-3 position of lead compound 1and modifying phenyl ring of quinazolin-2,4-dione core resulted in modest reduction against HDAC6 inhibitory activities and cytotoxicity. Among different lengths of linker at 2-position, compound 20 with benzyl linker displayed HDAC6 IC50 at 0.7 nM with 1700-fold selectivity to HDAC6 versus HDAC1 and IC50 at 0.83 μM against brain cancer cell line. In the final part, mimics of tricyclic core of Tubastatin A showed increased inhibitory activity against HDAC6, but only displayed cytotoxicity at micromolar range. With potent inhibitory activities against HDAC6 and brain cancer cell line, compound 5h and 20 may serve as leads for development of potential therapeutic agents against glioblastoma.