Synthesis And Bioevaluation Of Novel Histone Deacetylase Inhibitors And Diaryliodonium-derived Drug-Like Molecules As Anticancer Agents

Part 1 Design,Synthesis and Bioevaluation of Novel Histone Deacetylase Inhibitors as Anticancer AgentsEpigenetics play an essential role in the occurrence and development of cancer.In recent years,the development of small molecules targeting epigenetic pathways has become a hot spot in anticancer drug discovery.In particularly,histone acetylase(HDAC)inhibitors have shown excellent therapeutic effects on a variety of hematological tumors.However,the marketed HDAC inhibitors have several disadvantages such as inevitable drug-resistance and dose-limiting adverse effects.Therefore,the search for new strategies that can potentially overcome these challenges has been intensified,for example,the development of isoform-selective HDAC inhibitors and HD AC-based dual-acting inhibitors.In the second chapter,a series of 2-phenylthiazole or 2-phenylimidazole analogues were designed and synthesized based on a known HDAC6 inhibitor CAY 10603.Among them,XP5 was identified as the most potent HDAC6 inhibitor with an IC50 of 31 nM and excellent HDAC6 selectivity(SI=338).XP5 also displayed high antiproliferative potency against various cancer cell lines including an HDAC-resistant gastric cancer cell line(YCC3/7)with IC50 values in the range of 0.16-2.31 ?M,better than CAY10603.In addition,XP5 exhibited significant antitumor efficacy in a melanoma tumor model with a TGI(Tumor Growth Suppression)of 63%at 50 mg/kg without apparent toxicity.Furthermore,XP5 increased the expression of acetylated-?-tubulin significantly in tumor tissues.Moreover,XP5 efficiently enhanced the in vivo antitumor immune response when combined with a PD-L1 inhibitor,as demonstrated by the increased tumor-infiltrating lymphocytes and the reduced PD-L1 expression level.Taken together the above results suggest that XP5 is a promising HDAC6 inhibitor deserving further investigation.In the third chapter,a novel dual HDAC3/tubulin inhibitors were designed and efficiently synthesized by combining the pharmacophores of SMART(Tubulin inhibitor)and MS-275(HDAC inhibitor),among which,compound 15c was found to be the most potent and balanced HDAC3/tubulin dual inhibitor with high HDAC3 activity(IC50=30 nM)and selectivity(SI>1000)as well as excellent anti-proliferative potency against various cancer cell lines including an HDAC-resistant gastric cancer cell line(YCC3/7)with IC50 values in the range of 30-144 nM.Compound 15c inhibited B16-F10 cancer cell migration and colony formation.In addition,15c demonstrated significant in vivo antitumor efficacy in a B16-F10 melanoma tumor model with a better TGI(70.00%,10 mg/kg)than that of the combination of MS-275 and SMART.Finally,15c presented a safe cardiotoxicity profile and did not cause nephro-/hepatotoxicity.Collectively,this work shows that compound 15c represents a novel tubulin/HDAC3 dual-targeting agent deserving further investigation as a potential anticancer agent.Part 2 Synthesis and Biological Study of Diaryliodonium-derived Drug-Like MoleculesIn chapter 2 of this part,we successfully developed a copper-catalyzed C-N coupling between diaryliodonium salts and nitriles to construct diarylmethane amides.The inexpensive catalyst CuCl and hydrogen proton donor water are used in this procedure,which provided the target compounds with high yields.The reaction exhibited excellent functional group compatibility with aromatic nitriles,aliphatic-nitriles,and heterocyclic nitrile.Compounds 3k and 3s as the representative compounds showed excellent neuroprotective and anticancer activity.This is the first report for the construction of diarylmethane amides by C-N bond coupling with diaryliodonium salts as a safe and efficient arylation reagent.In chapter 3 of this part,we successfully developed a copper-catalyzed double C-N coupling reaction of diaryliodoniums and nitriles to form N-carbonyl acridine compounds.This reaction has good substrate universality.In addition,compound 7i showed good tubulin inhibitory activity and anticancer activity,thus deserving further investigation.