Development Of (S)-2-phenyl-2-(Phenylsulfonamido)Acetamide-based Histone Deacetylase Inhibitors

Epigenetic abnormality, caused by different modifications of DNA and histones instead of changes of nucleotide sequence, has been recognized to be widely implicated in tumor initiation and progression, and its manipulation holds great promise for cancer prevention, detection and therapy. Histone deacetylase (HDAC), a histone modifier catalyzing the removal of acetyl groups from N-acetyl lysine residues of chromatin histones, allows the histones to wrap DNA more tightly and finally leads to the repression of some tumor suppressor genes.So far, eighteen HDACs have been identified in humans. Since different HDAC isoforms have diverse biological targets and functions, pursuing potent HDAC inhibitors (HDACIs)with high activity, low toxicity and isoform selectivity has become the hot topic in epigenetics of antitumor research.Most HDACIs have three pharmacophore domains, a Zn2+ binding group (ZBG) which can go deep into the active site, a hydrophobic cap group (Cap) which can bond to hydrophobic amino acid residues on the surface of the active site and a hydrophobic linker which concatenate the ZBG and the Cap. Up to now, dozens of structurally diverse HDACIs have entered various stages of clinical trials. Among them,4 HDACIs have been approved by the US Food and Drug Administration (FDA) and 3 of them are hydroxamic acids. In addition, the class I selective HDACI chidamide (CS055) was approved by the China Food and Drug Administration (CFDA) for treatment of relapsed or refractory peripheral T-cell lymphoma.Many researches indicated that HDACIs with branched cap seemed to be more potent and isoform selective due to the additional hydrophobic interactions between the branched cap group and the amino acid residues around the entrance of the HDAC active site. In our previous study, three series of L-phenylglycine-containing cap HDACIs were discovered to have good performance in HDAC inhibitoryand in vitroantitumor evaluation. Combined with the discoveries of Daniel Delorme and Ivars Kalvinsh, a novel series of HDACIs with L-phenylglycine-containing branched cap were designed and synthesized using N-hydroxycinnamamide as linker and ZBG and sulfamide as connection unit. And different effects of different substituents in branched cap on inhibitory acticity were discussed.In this paper, we sythesized 20 novel compounds which were identified through HRMS and 1H-NMR or other methods and conducted the primary antitumor activity and structure-activity relationship evaluation. Our results showed that most target compounds have potent HDACs inhibitory activity equal to SAHA. Among them, 10k, 10r and 10s were superior to SAHA, whilecomparable to PXD101. However, all of the target compounds exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA.Representative compound 10s showed similar HDACs isoform selective profile to PXD101, demonstrating that it is a nonselective HDACI.