CAP rigidification of MS-275 and chidamide leads to enhanced antiproliferative effects mediated through HDAC1, 2 and tubulin polymerization inhibition

The study focuses on the prudent design and synthesis of anilide type class I HDAC inhibitors employing a functionalized pyrrolo[2,3-d]pyrimidine skeleton as the surface recognition part. Utilization of the bicyclic aromatic ring to fabricate the target compounds was envisioned to confer rigidity to the chemical architecture of MS-275 and chidamide. In-vitro enzymatic and cellular assays led to the identification of compound 7 as a potent inhibitor of HDAC1 and 2 isoform that exerted substantial cell growth inhibitory effects against human breast MDA-MB-231, cervical HeLa, breast MDA-MB-468, colorectal DLD1, and colorectal HCT116 cell lines with an IC50 values of 0.05-0.47 mu M, better than MS-275 and chidamide. In addition, the anilide 7 was also endowed with a superior antiproliferative profile than MS275 and chidamide towards the human cutaneous T cell lymphoma (HH and HuT78), leukemia (HL60 and KG-1), and HDACi sensitive/resistant gastric cell lines (YCC11 and YCC3/7). Exhaustive exploration of the construct 7 confirmed it to be a microtubule-targeting agent that could trigger the cell-cycle arrest in mitosis. In pursuit of extracting the benefits of evidenced microtubule-destabilizing activity of the anilide 7, it was further evaluated against non- small-cell lung cancer cell lines as well as the multiple-drug resistant uterine cancer cell line (MES-SA/Dx5) and overwhelmingly positive results in context of inhibitory effects were attained. Furthermore, molecular modelling studies were performed and some key interactions of the anilide 7 with the amino acid residues of the active site of HDAC1 isoform and tubulin were figured out. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

The study focused on the design and synthesis of anilide type class I HDAC inhibitors, leading to the discovery of compound 7 as a potent inhibitor with significant cell growth inhibitory effects against various tumor cell lines. Compound 7 was found to trigger cell-cycle arrest and microtubule-targeting activity, showing superior antiproliferative profile compared to existing HDAC inhibitors.