Design,Synthesis And Anti-Tumor Evaluation Of Novel Histone Deacetylase Inhibitors

Histone deacetylases inhibitor(HDACI)is emerging as a new strategy in human cancer therapy.Recently,3 HDACI drugs have been approved by FDA for the treatment of cancer,and many other drugs are in clinical trials.Today,benzamide-type compounds as HDACI candidates are widely studied with the advantages of improved anti-cancer efficacy and weaker toxicity.Therefore,the design and synthesis of novel HDACI compounds have become our major goals.Based on the previous work of our lab and the structures of clinical drugs,2 series(A and B)of novel benzamide-type compounds were designed,synthesized and evaluated for bio-screening,including 15 compds and 9 compds for class A and B respectively.All the intermediates and products were confirmed by TLC,MS and 1H-NMR.In the in vitro biological evaluation,SIPI7046 presented comparable inhibit activity towards HDAC1 enzyme and cancer cells to reference drug.Exceptly,SIPI7046 also presented low toxicity,non-cardiotoxicity and higher bioavailability,and these results encourage us to put it for further study.The reference HDACI drugs MS-275,MGCD0103 and SAHA were synthesized in good yields by using improved procedures.These not only provided highly pure reference drugs for bio-screening,also created prastical value for the process development of these listed drugs.This work enriched the structures of HDACI and provided significant reference for the studies of HDACI and further design of novel HDACI with high potency and good safty profiles.