Design, Synthesis And Activity Study Of Novel HDAC Dual-target Inhibitor

Acetylation is the most common post-translational modification of histones,which can regulate gene transcription by regulating chromatin conformation.Studies have pointed out that histone acetylation is mainly governed by two enzymes,among which histone acetyltransferase(HAT)can transfer the acetyl group derived from acetyl coenzyme A to the histone lysine(Lys)residues,resulting in a loose chromatin conformation and recruitment of transcription factors to promote gene transcription;In contrast,the histone deacetylase(HDAC)can remove the acetyl group away from the lysine residues in the core of histone,making the chromatin structure tight,thus leading to the transcriptional inhibition of tumor suppressor genes,and finally leading to the occurrence of tumors.At present,a variety of HDAC inhibitors have been approved,and they do not show significant therapeutic effects in solid tumors,but they still need to be further explored in solid tumors.Therefore,it is of great significance to design novel HDAC inhibitors for solid tumors.In this paper,the existing marketed drugs or compounds reported in the literature that can target other targets and show good anti-tumor activity are used as the parent core structure(Cap)of dual targeting inhibitors,and two different series of HDAC dual targeting inhibitors were designed and synthesized by connecting with the zinc binding group(ZBG)that can exert HDAC inhibitory activity.1.Design,Synthesis and Activity Study of a Novel Gemcitabine Prodrug Combined with a HDAC6 InhibitorIn this study,gemcitabine was selected as the parent core of the compound,and a new gemcitabine prodrug was designed and synthesized.Gemcitabine is a first-line drug for the treatment of pancreatic cancer and non-small cell lung cancer,and its anti-tumor activity has been confirmed for a long time.In this experiment,a new gemcitabine prodrug GZ combined with a HDAC6 inhibitor was obtained by modifying the4-position amino group of gemcitabine and connecting with a pentadecanoic acid,a selective HDAC6 inhibitor.Through the anti-tumor cell proliferation experiment,western blot experiment and in vivo animal experiment,it was proven that compound GZ has good anti-tumor activity,superior to gemcitabine in inhibiting tumor cell proliferation and inducing DNA damage.However,the drug resistance of gemcitabine was significantly improved by GZ through drug combination experiment.Liver microsomal enzyme inhibiton experiment and HE staining showed that there was no obvious side effects.2.Design,Synthesis and Activity Study of New Double target Inhibitors of HDAC6 and HSP90Heat shock protein 90(HSP90),as an energy dependent chaperone,can affect cell growth and survival by regulating its client proteins.In human body,HSP90 possesses more than 400 customer proteins,and most of them are closely related to the occurrence of tumors.On the other hand,HSP90,as the substrate of HDAC6,is regulated by HDAC6.When blocking the deacetylation of HSP90,the regulation of HSP90 to its client proteins was restricted which would prevent the occurrence of tumors.Therefore,HDAC6 inhibitors and HSP90 inhibitors have a synergistic effects.In this project,a new class of HSP90/HDAC dual inhibitors was designed with the key pharmacophore of the second generation HSP90 inhibitors,resorcinol as the cap group,and the hydroxamic acid as the ZBG.By changing different linkers and substituents at the 5 positions of the intermediate amino and benzene rings,a series of HDAC and HSP90 dual targeting inhibitors are designed and verified by the enzyme activity evaluation and cell viability.A candidate compound 12 g with selective HDAC6 inhibitory activity came up,and it showed strong anti-proliferative activity against various solid tumors.