Abstract
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.
Keywords: Antiproliferative, cancer therapy, dihydrofolate reductase inhibitors, dual enzyme inhibitors, folates and antifolates, histone deacetylase inhibitors, methotrexate, Folate-Hydroxamate, Antimetabolites
Medicinal Chemistry
Title: Novel Folate-Hydroxamate Based Antimetabolites: Synthesis and Biological Evaluation
Volume: 7 Issue: 4
Author(s): 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
Affiliation:
Keywords: Antiproliferative, cancer therapy, dihydrofolate reductase inhibitors, dual enzyme inhibitors, folates and antifolates, histone deacetylase inhibitors, methotrexate, Folate-Hydroxamate, Antimetabolites
Abstract: 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.
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P. Carrasco Marta, A. Enyedy Eva, I. Krupenko Natalia, A. Krupenko Sergey, Nuti Elisa, Tuccinardi Tiziano, Santamaria Salvatore, Rossello Armando, Martinelli Adriano and Amelia Santos M., Novel Folate-Hydroxamate Based Antimetabolites: Synthesis and Biological Evaluation, Medicinal Chemistry 2011; 7 (4) . https://dx.doi.org/10.2174/157340611796150923
DOI https://dx.doi.org/10.2174/157340611796150923 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
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Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
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