The Design And Synthesis Of Novel Histone Deacetylase Inhibitors

Histone deacetylases （HDAC） and histione acetyltransferases （HAT） playfundamental roles in the regulation of gene expression and maintenance of chromatinstructures. It is reported that the aberrant expression of histone deacetylases leads tohypoacetylation of histones, which is closely related to the occurance anddevelopment of cancer. Histone deacetylase inhibitors can reverse the hypoacetylationstatus of histones, thereby inducing the tumor cell differentiation and apoptosis. It hasbeen widely recognized in recently years that HDACs are promising targets forcancer therapy. In preclinical studies, several classes of HDACi have been found toexhibit potent and selective activities against tumor cells. Some of them havedemonstrated promising therapeutic potential in early-phase clinical trials forhaematological malignancies such as cutaneous T-cell lymphoma, myelodysplasticsyndromes and diffuse B-cell lymphoma. Subereyl anlide hydroxamic acid （SAHA）was the first HDAC inhibitor approved by FDA in2006fot the treatment of cancer.Previously, we reported a click–chemistry based approach to the synthesis of anovel calss of HDAC inhibitors. The lead compound NSC746457(IC₅₀=104nM)was found to be as potent as SAHA (IC₅₀=67nM) in enzymatic assay. The firstround optimization of NSC746457was based on HDAC2-TSA crystal structureDocking of NSC746457into HDAC2acitive sites and comparing with theHDAC2-TSA complex suggested that the hydrophobic residue Phe210flanking thecap-group binding-motif could be explored for structural optimization.16compoundswere synthesized by introducing different hydrophobic group on the methylene groupof NSC746457and two more potent HDAC inhibitors was identified: isopropylderivative and tert-butyl derivative, with an IC₅₀value of22nM and18nM,respectively.Fourteen compounds were synthesized in the second round optimization ofNSC746457, including the replacement of trans-styryl moiety with a2-substitutedbenzo-hetero aromatic ring, and the introduction of a substititent onto the cental methylene carbon. A promising chiral lead, S-（E）-3-（1-（1-（Benzo[d]oxazol-2-yl）-2-methylpropyl）-1H-1,2,3-triazol-4-yl）-N-hydroxyacrylamide （12, NK-HDAC-1）, wasdiscovered, and showed about one order of magnitude more potent than SAHA in inboth enzymatic and cellular assays (IC₅₀of histone deacetylase inhibition,7nM;MTS GI50of56cancer cell lines,10⁵40nM). For the in vitro safty tests,NK-HDAC-1was far less toxic to normal breast cell MCF-10A. The physic-chemicalproperties （LogD and solubility） and in vitro ADME (including liver microsomalstability (t_1/2), plasma stability (t_1/2), apparent permeability and CYP-3A4inhibition)strongly suggested that NK-HDAC-1might be superior to SAHA in as a new oralHDACi candidate.