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Novel Folate-Hydroxamate Based Antimetabolites: Synthesis and Biological Evaluation

[ Vol. 7 , Issue. 4 ]


Marta P. Carrasco, Eva A. Enyedy, Natalia I. Krupenko, Sergey A. Krupenko, Elisa Nuti, Tiziano Tuccinardi, Salvatore Santamaria, Armando Rossello, Adriano Martinelli and M. Amelia Santos   Pages 265 - 274 ( 10 )


A set of hydroxamate derivatives of folic acid and methotrexate (MTX) was synthesized and evaluated for the inhibitory activity against histone deacetylase (HDAC) and dihydrofolate reductase (DHFR), two enzymes overexpressed in metastasizing tumors. The synthesized compounds were further screened for their antiproliferative activity in two human cancer cell lines, A549 (non-small cell lung carcinoma) and PC-3 (prostate adenocarcinoma). All derivatives showed significant inhibitory activity against HDACs (micromolar range) while only the MTX derivative was reasonably effective in DHFR inhibition. A docking study provided insight into the binding mode of the most potent inhibitor in the active sites of the enzymes, allowing rationalization of the bioassays. The MTX-based compound could be of interest for testing against metastasizing tumors in an animal model. The studied derivatives represent promising molecular templates for further development of dual activity anti-cancer drugs.


Antiproliferative, cancer therapy, dihydrofolate reductase inhibitors, dual enzyme inhibitors, folates and antifolates, histone deacetylase inhibitors, methotrexate, Folate-Hydroxamate, Antimetabolites


Centro de Quimica Estrutural, Instituto Superior Tecnico, 1049-001 Lisboa, Portugal.

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