2. Academic Validation
  3. Quinoline-Based DNA Methyltransferase Inhibitors Featuring Basic Side Chains: Design, Synthesis, and Insight in Biochemical and Anticancer Cell Properties

Quinoline-Based DNA Methyltransferase Inhibitors Featuring Basic Side Chains: Design, Synthesis, and Insight in Biochemical and Anticancer Cell Properties

  • J Med Chem. 2025 Nov 27;68(22):23886-23909. doi: 10.1021/acs.jmedchem.5c01029.
Clemens Zwergel 1,  Chiara Lambona 1,  Rossella Fioravanti 1,  Alessia Raucci 1,  Francesco Fiorentino 1,  Guilaine Nchugoua Tchieh 2,  Corinne Jallet 2,  Laurent Lacroix 3,  Michela Pierrettori 4,  Francesca Romana Pellegrini 4,  Yan Xiong 5,  Jian Jin 5,  Paola Arimondo 2,  Daniela Trisciuoglio 4,  Antonello Mai 1,  Sergio Valente 1
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
  • 2 Université Paris Cité, CNRS UMR no 3523 Chem4Life, Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, F-75015 Paris, France.
  • 3 IBENS, Département de biologie, École Normale Supérieure, Université PSL, CNRS, INSERM, Paris 75005, France.
  • 4 IBPM Institute of Molecular Biology and Pathology, CNR National Research Council of Italy, Via degli Apuli 4, Rome 00185, Italy.
  • 5 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Science, Oncological Science and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
PMID: 41217771 DOI: 10.1021/acs.jmedchem.5c01029
Abstract

The quinoline DNMT inhibitors 4-21, incorporating basic chains, were designed, synthesized, and evaluated for their ability to inhibit DNMT1 and DNMT3A/3L by directly measuring DNA methylation. Pharmacomodulation yielded nanomolar inhibitors with selectivity for either DNMT1 or DNMT3A/3L. The meta/meta analogs 7-14 exhibited the highest inhibition, with compounds 10 and 14 being the most potent and selective for DNMT3A/3L and DNMT1, respectively. DNA thermal denaturation experiments demonstrated for selected compounds strong DNA interaction. COBRA analysis in HCT-116 colon Cancer cells revealed a selective reduction in P16INK4A methylation, a tumor suppressor gene reactivated by DNMT inhibition. Among the tested Cancer cell lines, HCT-116 was the most sensitive, and 14 showed the strongest antiproliferative effect. In isogenic HCT-116 P53-/- cells, 14 exhibited reduced antiproliferative activity, lower Apoptosis, and decreased levels of cleaved Caspase 3, P53, and γH2AX, confirming its P53-dependent mechanism of action linked to DNA damage.

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