Synthesis and In Vitro Pharmacological Evaluation of 5,8-Dideaza Analogs of Methotrexate
This study describes the synthesis of a series of dideaza analogs of methotrexate and their preliminary pharmacological and metabolic evaluation. The 5,8-dideazamethotrexate was efficiently obtained in five steps using a new synthetic route. Oxygenated and thiolated analogs of dideazamethotrexate were prepared following the devised pathway. Their cytotoxicity was studied in the A549 lung cancer cell line, as well as their DHFR dihydrofolate reductase inhibition activity and in vitro metabolism. The two new analogs showed strong activity on cancer cells and the enzymatic target. These compounds were not metabolized, a clear advantage over methotrexate, which is rapidly converted to the toxic metabolite 7-hydroxymethotrexate.
Authors
- Dáire Gibbons (ORCID: https://orcid.org/0000-0001-9897-2016)
- Charles Skarbek (ORCID: https://orcid.org/0000-0003-0054-2064)
- Estelle Rascol (ORCID: https://orcid.org/0000-0002-2301-6107)
- Raphaël Labruère (ORCID: https://orcid.org/0000-0003-3683-2768)
- Marta Abellán-Flos (ORCID: https://orcid.org/0000-0002-0981-4698)
- Ainhoa García (ORCID: https://orcid.org/0000-0001-8561-6311)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Inserm (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Chimie et Biologie des Membranes et des Nanoobjects (FR)
- Institut de Chimie Moléculaire et des Matériaux d'Orsay (FR)
- Institut Polytechnique de Bordeaux (FR)
- Institut Curie (FR)
Publication Details
- Journal
- Molecules
- Published
- 2025-06-27
- DOI
- https://doi.org/10.3390/molecules30132772
- Primary Topic
- Synthesis and biological activity
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Fondation ARC pour la Recherche sur le Cancer
- CHIST-ERA