Design,Synthesis And Anticancer Activity Of Vadimezan Derivatives And Lipoic Acid-based Vorinostat Analogues

Cancer has been the "First Killer" threatening human health.This dissertation focused on design,synthsis and anticancer evaluation of Vadimezan derivatives and lipoic acid-based Vorinostat analogues.Although Novartis has announced the failure of Phase Ⅲ trial of Vadimezan treating lung cancer,the small molecule as a tumor vascular disrupting agent still has the value of further investigation on structure modification.It is able to disrupt blood vessels around tumor cells,cut off neutrition supply,and therefore,inhibit tumor growth.In this part of dissertation,fifty-eight Vadimezan esters,amides,arylidene hydrazides,diacylhydrazides,acyl thiosemicarbazides and hydrazones have been designed,synthesized and characterized by IR,1H NMR,MS,HRMS or elemental analysis,and XRD.All compounds have evaluated their in vitro anticancer activities,including BGC-823,BEL-7402,HL-60,Jeko-1,A549,SK-BR-3,Ishikawa,Bewo,HeLa,Siha,MCF-7 and NCI-460 cancer cell lines,best of which are compounds 1-27,1-28 and 1-43,who have IC50s of 9.39 μM,10.82 μM and 11.52 μM against A549,respectively,even better than that of CA-4.While compounds 1-26 and 1-43 have IC50s of 4.56 μM and 20.83μM against HL-60,mixture of 1-58 and 1-61 isomers have an IC50 of 7.01 μM against NCI-460,better than that of DDP.Selected compounds 1-6,1-22 and 1-26 have been evaluated their in vivo antitumor efficacy against S180 xenograft in ICR mice,and the results showed that at the dose of 200 mg/kg,compound 1-22 has an inhibition rate of 25.75%.Vorinostat has been approved by FDA as an HD AC inhibitor,treating cutaneous T-cell lymphoma,since 2006.Lipoic acid and its derivatives are considered as potential antitumor agents with very low toxicity.In this part of dissertation,we have analysized the structural features of Vorinostat and lipoic acid,designed and synthesized fifty-one lipoic acid-based Vorinostat analogues,including 6,8-bis(acylthio)octanoicacids,hydroxamates,lipoamides,and confirmed their structures by IR,1H NMR,MS,HRMS or elemental analysis.All compounds have their in vitro anticancer activities tested,including NCI-460,HO-8910,KB,BEL-7402,PC3,Ishikawa,A549,Bewo,HeLa,Siha,MCF-7 and HL-60 cancer cell lines,and several compounds have better inhibitions than Vorinostat at the dose of 100 μg/mL.Compound 2-23 has been evaluated in vivo antitumor efficacy agaist S180 xenograft in mice,which has 24.68%tumor-weight inhibition through intragastric administration of 200 mg/kg of body weight.Moreover,the LD50 in mice for 2-23 exceeded 1000 mg/kg.The MTD of 2-23 following intraperitoneal dosed at 100 mg/kg,showing neither morality nor significant body weight loss.In addition,we have designed,synthesized Vorinostat analogues without thiol side chain at C6 position.Comparing the result of their anticancer activities and molecular docking,it is found that compounds without thiol side chain at C6 position should be HDAC inhibitors,whilst our synthesized lipoic acid derivatives are unable to access the active site of HDAC,and might have other targets.