Rational Design,Synthesis And Biological Evaluation Of HDAC-based Dual-target Inhibitors

Modern drug discovery has been strongly focused on the development of drugs acting on a specific target with high potency and selectivity.However,single target durgs might not achieve the desired effect for the treatment of complex diseases such as cancer.In recent years,with the development of polypharmacology and deep understanding of tumor pathogenesis,multi-targeting antitumor agents have been considered as an important strategy to overcome drug resistance and improve therapeutic effects.Histone deacetylases(HDACs)is a family of important therapeutic targets for cancer treatment,which can serve as a good starting point to design multi-targeting antitumor agents.HDAC inhibitors(HDACi)can synergistically enhance the inhibitory effect of other antitumor agents,such as Nampt,p53-MDM2,Hsp90 and tubulin inhibitors.The synergistic effects of HDACi with other antitumor agents have been used as a effective strategy to design dual-target inhibitors.Several promising HDACi-based compounds are under pre-clinical or clinical investigation.This thesis mainly includes two parts:(1)Rational design,synthesis and biological evaluation of HDAC/Nampt dual-target inhibitors;(2)Rational design,synthesis and biological evaluation of p53-MDM2/HDAC dual-target inhibitors.1.Rational design,synthesis and biological evaluation of HDAC/Nampt dual inhibitorsHDACi and Nampt inhibitors shared similar structures and showed synergistic effects on cancer.On the basis of the structural features of both HDACi and Nampt inhibitors,novel dual HDAC/Nampt inhibitors were rationally designed.A total of 62 new derivatives were synthesized.Enzyme inhibitory assay revealed that most of the target compounds showed good HDAC/Nampt dual inhibitory activity.Some of them exhibited excellent activity against both HDAC1 and Nampt at nanomolar levels with balanced activities.Compound 12 j displays potent in vitro inhibitory activity against Nampt and HDAC1 with an IC50 of 24 nM and 1 nM,respectively.Compound 14 d possessed the best balanced activities against both Nampt and HDAC with the IC50 value of 31 nM and 51 nM,respectively.Moreover,these highly potent compounds(12j and 14b)can effectively induce the apoptosis of HCT116 cells.In addition,Western blot assay show displayed that compound 12 j and 14 b significantly increased tumor cell histone acetylation levels.At the dose of 25 mg/kg,compounds 12 j and 14 b reduced 68.88% and 52.71% tumor growth,respectively.They represent promising candidates for the development of novel antitumor agents.2.Rational design,synthesis and biological evaluation of p53-MDM2/HDAC dual-target inhibitorsp53-MDM2 inhibitors exhibited synergistic anticancer effect when they were combined with HDACi.Based on the structural features of both p53-MDM2 inhibitors and HDACi,novel dual p53-MDM2/HDAC inhibitors were rationally designed.As a result,7 new compounds were synthesized.As compared with the reference drug,some of the target compounds showed improved in vitro antitumor activity.Compound 15 d showed excellent anti-HDAC1 activity with the IC50 value of 9 nM.These results validated the possibility of designing p53-MDM2/HDAC dual inhibitors and lay a foundation for further studies.