Improved Synthesis Of Rocilinostat And Design,Synthesis And Activity Evaluation Of HDAC Inhibitions With Branched Cap

Epigenetic regulation as a posttranslational modification,which does not involve DNA sequence changes but can be inherited,closely related to cell proliferation,differentiation and apoptosis.Histones modification play an important role in epigenetic regulation,because it can regulate the chromatin state,thus affecting the gene expression.Histone acetylation modification is one of the important way,which is balanced by histone acetyltransferases(HATs)and histone deacetylases(HDACs).To date,four classes of 18 mammalian HDACs have been identified:Class I(HDAC 1～3,8),Class Ⅱ(Ila:HDAC 4,5,7,9,Ⅱb:HDAC 6,10),Class III(SIRT 1～7)and Class Ⅳ(HDAC 11).The current study shows that HDAC subtypes are closely related to the occurrence and development of various diseases,including tumors,neurodegenerative diseases,inflammation,cardiac diseases.Thus becoming an important target for drug development.Currently,five HDAC inhibitors have been approved by the FDA or CFDA as anti-cancer drugs,which are vorinostat,romidepsin,panobinostat,belinostat and chidamide.In addition,there are a dozen of HDACIs in different phases of clinical research.However,most of these inhibitors are pan-HDACls or multi-isoform-selective and thus may have some side effects resulting from the off-target effect of pan-HDACIs.Rocilinostat is a selective HDAC 6 inhibitor developed by Celgene and is currently in Phase Ⅱ clinical trials combined with bortezomib for the treatment of relapsed and refractory multiple myeloma.In preclinical studies,rocilinostat shows good pharmacokinetic and pharmacodynamic properties and therefore has good prospects for drug use.In this project,we optimize the synthesis process of rocilinostat on the basis of the original route and make it to meet the requirements of industrial production.In addition,inspired by the structure of rocilinostat and compounds llr and 12m previously studied by our group,we have designed a class of HD AC inhibitors with novel scaffolds that have branched Cap group.In vitro inhibition experiments showed that the representative compounds 9o,9p,9q and 9t were significantly superior to positive control SAHA,PXD-101 and ACY-1215,but showed no obvious HDAC isoforms selectivity.Meanwhile,these compounds showed comparable bioactivity compared to positive control SAHA and ACY-1215 in anti-tumor cell proliferation experiment.In summary,this project optimized the synthesis route of rocilinostat to meet the production requirements,and also screened several highly active broad-spectrum HDAC inhibitors.It is expected that the anti-tumor drug candidates will be further studied on this basis.