Abstract
Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) are newer antifolates that specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-γ-glutamate synthetase (FPGS). Recently, classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed (6) and GW1843 (7). Nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)} are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS, DHFR, FPGS, and RFC have been proposed. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates were discussed in Part I. The 6-6 bicyclic and tricyclic antifolates will be discussed here in Part II.
Keywords: Thymidylate Synthase (TS), Dihydrofolate Reductase (DHFR), Folate, Antifolates, Classical, Nonclassical, Inhibitors, Pathogens
Anti-Cancer Agents in Medicinal Chemistry
Title: Recent Advances in Classical and Non-Classical Antifolates as Antitumor and Antiopportunistic Infection Agents: Part II
Volume: 8 Issue: 2
Author(s): Aleem Gangjee, Hiteshkumar D. Jain and Sonali Kurup
Affiliation:
Keywords: Thymidylate Synthase (TS), Dihydrofolate Reductase (DHFR), Folate, Antifolates, Classical, Nonclassical, Inhibitors, Pathogens
Abstract: Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) are newer antifolates that specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-γ-glutamate synthetase (FPGS). Recently, classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed (6) and GW1843 (7). Nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)} are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS, DHFR, FPGS, and RFC have been proposed. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates were discussed in Part I. The 6-6 bicyclic and tricyclic antifolates will be discussed here in Part II.
Export Options
About this article
Cite this article as:
Gangjee Aleem, Jain D. Hiteshkumar and Kurup Sonali, Recent Advances in Classical and Non-Classical Antifolates as Antitumor and Antiopportunistic Infection Agents: Part II, Anti-Cancer Agents in Medicinal Chemistry 2008; 8 (2) . https://dx.doi.org/10.2174/187152008783497064
DOI https://dx.doi.org/10.2174/187152008783497064 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- 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
-
Strategies for In Vivo siRNA Delivery in Cancer
Mini-Reviews in Medicinal Chemistry Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer
Current Molecular Medicine Effect of Cytostatic Drugs on the mRNA Expression Levels of Ribonuclease κ in Breast and Ovarian Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry Effect of Soy Isoflavone Supplementation on Endothelial Dysfunction and Oxidative Stress in Equol-Producing Postmenopausal Women
Endocrine, Metabolic & Immune Disorders - Drug Targets Human Sirtuins: An Overview of an Emerging Drug Target in Age-Related Diseases and Cancer
Current Drug Targets Applications of Nanosystems to Anticancer Drug Therapy (Part II. Dendrimers, Micelles, Lipid-based Nanosystems)
Recent Patents on Anti-Cancer Drug Discovery Long Non-Coding RNAs As Epigenetic Regulators in Cancer
Current Pharmaceutical Design Anionic Antimicrobial Peptides from Eukaryotic Organisms
Current Protein & Peptide Science Understanding the Basis for the Association of apoE4 with Alzheimers Disease: Opening the Door for Therapeutic Approaches
Current Alzheimer Research Anticancer Drug Development, System Updating and Global Participations
Current Drug Therapy Jade-1: its structure, regulation and functions in the renal cancer.
Current Molecular Medicine Mesenchymal Stem Cells: Key Actors in Tumor Niche
Current Stem Cell Research & Therapy Calixarene: A Versatile Material for Drug Design and Applications
Current Pharmaceutical Design Synthesis of Novel 2,3,4-trisubstituted-oxazolidine Derivatives and In Vitro Cytotoxic Evaluation
Medicinal Chemistry Therapeutic Applications of Capsaicin in Upper Airways
Current Drug Targets Microenvironment and Brain Tumor Stem Cell Maintenance: Impact of the Niche
Anti-Cancer Agents in Medicinal Chemistry Targeting Transient Receptor Potential Channels in Cardiometabolic Diseases and Myocardial Ischemia Reperfusion Injury
Current Drug Targets The Chemical Defensive System in the Pathobiology of Idiopathic Environment- Associated Diseases
Current Drug Metabolism Quantum Noise Removal from Breast Mammograms Using Genetic Programming based Hybrid Ensemble Filter
Current Medical Imaging Emerging Technologies for Fertility Preservation in Female Patients
Current Women`s Health Reviews