2. Academic Validation
  3. Design and Synthesis of Topoisomerases-Histone Deacetylase Dual Targeted Quinoline-Bridged Hydroxamates as Anticancer Agents

Design and Synthesis of Topoisomerases-Histone Deacetylase Dual Targeted Quinoline-Bridged Hydroxamates as Anticancer Agents

  • J Med Chem. 2025 Feb 13;68(3):2849-2868. doi: 10.1021/acs.jmedchem.4c02135.
Gaurav Joshi 1,  Umesh Prasad Yadav 2,  Zahid Rafiq 3,  Preeti Grewal 4,  Manvendra Kumar 1,  Tashvinder Singh 2,  Vibhu Jha 5 6,  Praveen Sharma 2,  Leif A Eriksson 5,  Lenkalapelly Srinivas 7,  Nilesh Lakshman Dahibhate 7,  Pratima Srivastava 7,  Priyadeep Bhutani 7,  Uttam Kumar Mishra 8,  Ashoke Sharon 8,  Uttam C Banerjee 4,  Nisha Sharma 3,  Joydeep Chatterjee 1,  Kulbhushan Tikoo 3,  Sandeep Singh 2,  Raj Kumar 1
Affiliations

Affiliations

  • 1 Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, School of Pharmaceutical Sciences, Central University of Punjab, Bathinda 151 401, India.
  • 2 Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, India.
  • 3 Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar 160062, India.
  • 4 Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research, S.A.S. Nagar 160062, India.
  • 5 Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg 405 30, Sweden.
  • 6 Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, University of Bradford, Bradford BD7 1DP, U.K.
  • 7 Aragen Life Sciences, DMPK division, Hyderabad 500 076, India.
  • 8 Department of Chemistry, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
PMID: 39808731 DOI: 10.1021/acs.jmedchem.4c02135
Abstract

The multifactorial nature of Cancer requires treatment that involves simultaneous targeting of associated overexpressed proteins and cell signaling pathways, possibly leading to synergistic effects. Herein, we present a systematic study that involves the simultaneous inhibition of human topoisomerases (hTopos) and histone deacetylases (HDACs) by multitargeted quinoline-bridged hydroxamic acid derivatives. These compounds were rationally designed considering pharmacophoric features and catalytic sites of the cross-talk proteins, synthesized, and assessed for their Anticancer potential. Our findings revealed that the compound 5c significantly produced Anticancer effects in vitro and in vivo by reducing the tumor growth and its size in the A549 cell-induced lung Cancer xenograft model through multiple mechanisms, primarily by multi-inhibition of hTopoI/II and HDACs, especially HDAC1 via atypical binding. The present paper discusses detailed mechanistic biological investigations, structure-activity effects supported by computational docking studies, and DMPK studies and provides future scope for lead optimization and modification.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168477
    HDAC1 Inhibitor