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.
Export Options
About this article
Cite this article as:
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 |
Call for Papers in Thematic Issues
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
Recent Advances in the Medicinal Chemistry of Cancer
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
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Arginyl Aminopeptidase-Like 1 (RNPEPL1) Is an Alternatively Processed Aminopeptidase with Specificity for Methionine, Glutamine, and Citrulline Residues
Protein & Peptide Letters Are Selenoproteins Important for the Cancer Protective Effects of Selenium?
Current Nutrition & Food Science Recent Advances in Nanosystems and Strategies for Managing Leishmaniasis
Current Drug Targets A Novel Series of N-aryltriazole and N-acridinyltriazole Hybrids as Potential Anticancer Agents
Current Organic Synthesis Obstetrician-Gynecologists’ Practices, Statistical Literacy, and Risk Communication with Regard to Sexually Transmitted Infections
Current HIV Research Tumor-Induced Alterations in Lipid Metabolism
Current Medicinal Chemistry Cancer and Treatment Modalities
Current Cancer Therapy Reviews Deregulation of HOX B13 Expression in Urinary Bladder Cancer Progression
Current Medicinal Chemistry Interrelationships Among Gut Microbiota and Host: Paradigms, Role in Neurodegenerative Diseases and Future Prospects
CNS & Neurological Disorders - Drug Targets A Simple Identification of Novel Carbonyl Reducing Enzymes in the Metabolism of the Tobacco Specific Carcinogen NNK
Drug Metabolism Letters Natural Compounds with Proteasome Inhibitory Activity for Cancer Prevention and Treatment
Current Protein & Peptide Science Resisting the Resistance in Cancer: Cheminformatics Studies on Short- Path Base Excision Repair Pathway Antagonists Using Supervised Learning Approaches
Combinatorial Chemistry & High Throughput Screening Renal Cell Cancer and Positron Emission Tomography- an Evolving Diagnostic and Therapeutic Relationship
Current Medical Imaging Renaissance of the Biologically Active Vitamin A Derivatives: Established and Novel Directed Therapies for Cancer and Chemoprevention
Current Pharmaceutical Design MicroRNAs in Cancer: Small Molecules, Big Chances
Anti-Cancer Agents in Medicinal Chemistry Cytostatic and Apoptotic Effects of DNMT and HDAC Inhibitors in Endometrial Cancer Cells
Current Pharmaceutical Design MicroRNA Levels in Cervical Cancer Samples and Relationship with Lesion Grade and HPV Infection
MicroRNA Potentials of Polymeric Nanoparticle as Drug Carrier for Cancer Therapy: With a Special Reference to Pharmacokinetic Parameters
Current Drug Metabolism Hypomethylation of Urokinase (uPA) Promoter in Breast and Prostate Cancer: Prognostic and Therapeutic Implications
Current Cancer Drug Targets Nuclear Export as a Novel Therapeutic Target: The CRM1 Connection
Current Cancer Drug Targets