Design,Synthesis And Activity Study Of PARP/HDAC Dual Target Inhibitors

In recent years,the concept of multi-target drugs has been gradually strengthened,which plays an important role in the anti-tumor field by enhancing the efficacy through synergistic effects on multiple targets.Cancer is a mechanism of complex diseases,single target drugs are often only of a certain path to inhibit cancer development,other pathway activation can make up for the inhibition of a single channel,so the single target drug unsustainable,effectively control the cancer,and easy to produce drug resistance,on the contrary,at the same time more than inhibit cancer pathways have stronger and lasting antitumor effect.Poly ADP-ribose polymerase(PARP)is a DNA repair enzyme involved in many cellular processes.Abnormal expression of PARPs is associated with cancer,oxidative stress,inflammation and metabolic diseases,which makes PARP inhibitors(PARP inhibitors,PARPis is used to treat a variety of diseases.Histone deacetylase(HDAC)regulates tumor proliferation and metastasis by affecting gene transcription and ultimately affects the prognosis of patients.In the treatment of hematologic tumors,HDAC inhibitors(HDACis)have achieved significant efficacy,but have not achieved the expected effect in the treatment of solid tumors.In combination therapy,both PARPis and HDACis have shown the ability to sensitize tumor cells to other antitumor agents,and synergies have been observed in vitro and in vivo when working together on various cancer cells.HDACis can reduce the level of DNA damage response and down-regulate homology recombination(HRR)genes,leading to BRCAness,which is defined as a defect in homology recombination repair.Mimics the loss of BRCA1 or BRCA2)and enhances the biological activity of PARPis.Therefore,the combination of PARPis and HDACis is promising and will expand the number of cancer subtypes sensitive to PARPis.In this project,benzopyrazole and benzoimidazole are used as the structural parent nuclei to design and synthesize two series of 14 hydroxamic acid compounds.Benzimidazole and benzopyrazole have been reported in many literatures and patents as active structures of good PARP inhibitors such as Niraparib and Veliparib.Firstly,the enzyme inhibition activities of par P-1 protein and HDAC protein of the two targets were tested.A variety of tumor cell lines were selected to test the anti-proliferation activities,and1-8-6 and 1-8-7 with better comprehensive efficacy were selected for further testing.We concluded that 1-8-6 and 1-8-7 had a double inhibitory effect on PARP-1 and HDAC6,and the anti-proliferation IC50 value was in the micromole range.Compounds 1-8-6 and 1-8-7significantly inhibited the growth of tumor cells within 48 hours and 72 hours,which were superior to Olaparib,Tubastatin A and their combination.1-8-6 showed obvious antimigration and anti-angiogenesis activities.Reactive oxygen species(ROS)experiment results showed that 1-8-6 could significantly increase the ROS expression level,which proved that DNA damage could be induced.At the same time,Western blot test showed that 1-8-6 could promote the expression of acetylated α-tubulin,and had a relatively weak promotion effect on the degree of acetylation of histone H3 and H4.Finally,simulated docking results showed that 1-8-6 could fit the active sites of PARP-1 and HDAC6.All results indicated that 1-8-6 is a promising candidate for further preclinical studies.