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

Arshdeep Singh, Ting Yu Chang, Navdeep Kaur, Kai Cheng Hsu, Yun Yen, Tony Eight Lin, Mei Jung Lai, Sung Bau Lee, Jing Ping Liou

Research output: Contribution to journalArticlepeer-review

Abstract

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 μM, 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.

Original languageEnglish
Article number113169
JournalEuropean Journal of Medicinal Chemistry
Volume215
DOIs
Publication statusPublished - Apr 5 2021

Keywords

  • Epigenetic
  • HDACi resistance
  • Histone deacetylase inhibitors
  • Leukemia
  • Mmultiple drug resistance
  • Ssolid tumors
  • Tubulin inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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