Quinoline-Based DNA Methyltransferase Inhibitors Featuring Basic Side Chains: Design, Synthesis, and Insight in Biochemical and Anticancer Cell Properties
The quinoline DNMT inhibitors <b>4</b>-<b>21</b>, incorporating basic chains, were designed, synthesized, and evaluated for their ability to inhibit DNMT1 and DNMT3<i>A</i>/3L by directly measuring DNA methylation. Pharmacomodulation yielded nanomolar inhibitors with selectivity for either DNMT1 or DNMT3<i>A</i>/3L. The <i>meta</i>/<i>meta</i> analogs <b>7</b>-<b>14</b> exhibited the highest inhibition, with compounds <b>10</b> and <b>14</b> being the most potent and selective for DNMT3<i>A</i>/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 P16<sup>INK4A</sup> methylation, a tumor suppressor gene reactivated by DNMT inhibition. Among the tested cancer cell lines, HCT-116 was the most sensitive, and <b>14</b> showed the strongest antiproliferative effect. In isogenic HCT-116 P53<sup>-/-</sup> cells, <b>14</b> 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.
Authors
- Francesco Fiorentino (ORCID: https://orcid.org/0000-0003-3550-1860)
- Daniela Trisciuoglio (ORCID: https://orcid.org/0000-0002-7007-7914)
- Antonello Mai (ORCID: https://orcid.org/0000-0001-9176-2382)
- Clemens Zwergel (ORCID: https://orcid.org/0000-0002-3097-0003)
- Paola B. Arimondo (ORCID: https://orcid.org/0000-0001-5175-4396)
- Jian Jun Jin (ORCID: https://orcid.org/0000-0002-2387-3862)
- Yan Xiong (ORCID: https://orcid.org/0000-0003-0676-8267)
- Laurent Lacroix (ORCID: https://orcid.org/0000-0002-6382-9057)
- Francesca Romana Pellegrini (ORCID: https://orcid.org/0000-0003-4030-5127)
- Rossella Fioravanti (ORCID: https://orcid.org/0000-0002-9329-8234)
- Sérgio Valente (ORCID: https://orcid.org/0000-0002-2241-607X)
- Corinne Jallet
- Chiara Lambona (ORCID: https://orcid.org/0000-0002-3415-4126)
- Alessia Raucci (ORCID: https://orcid.org/0000-0003-4182-4420)
- Guilaine Nchugoua Tchieh
- Michela Pierrettori
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Institute of Molecular Biology and Pathology (IT)
- Tisch Hospital (US)
- Institut de Biologie de l'École Normale Supérieure (FR)
- Epigénétique et Destin Cellulaire (FR)
- Tisch Cancer Institute
- Sapienza University of Rome (IT)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01029
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00