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) 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). Novel antifolates have been developed that do not need to be polyglutamylated and include plevitrexed (6) and GW1843 (7). Nonclassical antifolates for antitumor and parasitic chemotherapy, such as nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)}, can passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Variations in the structures of antifolates have helped delineate the structural influence on the interaction with TS, DHFR, FPGS, and RFC utilization. The differences in the active site of human and pathogen DHFR have also been exploited. The literature contains excellent reviews on the design and synthesis of antifolates prior to 1996. 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 will be discussed in Part I, while 6-6 bicyclic and tricyclic antifolates will be discussed in Part II.
Keywords: Thymidylate Synthase (TS), Dihydrofolate Reductase (DHFR), Folate, Antifolates, Classical, Nonclassical, Inhibitors, Pathogen
Anti-Cancer Agents in Medicinal Chemistry
Title: Recent Advances in Classical and Non-Classical Antifolates as Antitumor and Antiopportunistic Infection Agents: Part I
Volume: 7 Issue: 5
Author(s): Aleem Gangjee, Hiteshkumar D. Jain and Sonali Kurup
Affiliation:
Keywords: Thymidylate Synthase (TS), Dihydrofolate Reductase (DHFR), Folate, Antifolates, Classical, Nonclassical, Inhibitors, Pathogen
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) 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). Novel antifolates have been developed that do not need to be polyglutamylated and include plevitrexed (6) and GW1843 (7). Nonclassical antifolates for antitumor and parasitic chemotherapy, such as nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)}, can passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Variations in the structures of antifolates have helped delineate the structural influence on the interaction with TS, DHFR, FPGS, and RFC utilization. The differences in the active site of human and pathogen DHFR have also been exploited. The literature contains excellent reviews on the design and synthesis of antifolates prior to 1996. 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 will be discussed in Part I, while 6-6 bicyclic and tricyclic antifolates will be discussed 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 I, Anti-Cancer Agents in Medicinal Chemistry 2007; 7 (5) . https://dx.doi.org/10.2174/187152007781668724
DOI https://dx.doi.org/10.2174/187152007781668724 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
-
Melatonin Regulates Angiogenic and Inflammatory Proteins in MDA-MB-231 Cell Line and in Co-culture with Cancer-associated Fibroblasts
Anti-Cancer Agents in Medicinal Chemistry Dyspnea in Cancer Patients: A Well-Known and Neglected Symptom
Reviews on Recent Clinical Trials Editorial: (Thematic Issue: Occupational Exposure: An Undermined Risk Factor of Lung Diseases in the Informal Sectors of Developing Economy)
Current Respiratory Medicine Reviews Epigenetics in Vascular Disease – Therapeutic Potential of New Agents
Current Vascular Pharmacology Tubulin Colchicine Binding Site Inhibitors as Vascular Disrupting Agents in Clinical Developments
Current Medicinal Chemistry Development of Sendai Virus Vectors and their Potential Applications in Gene Therapy and Regenerative Medicine
Current Gene Therapy In Vitro Regulatory Effect of Epididymal Serpin CRES on Protease Activity of Proprotein Convertase PC4/PCSK4
Current Molecular Medicine The ‘Other’ Telomerase Inhibitors: Non-G-Quadruplex Interactive Agent, Non-Antisense, Non-Reverse Transcriptase Telomerase Inhibitors
Current Medicinal Chemistry - Anti-Cancer Agents Mechanisms of Tubulin Binding Ligands to Target Cancer Cells: Updates on their Therapeutic Potential and Clinical Trials
Current Cancer Drug Targets Role of Iodine, Selenium and Other Micronutrients in Thyroid Function and Disorders
Endocrine, Metabolic & Immune Disorders - Drug Targets Towards Human on a Chip: Recent Progress and Future Perspective
Micro and Nanosystems Plant Ribonucleases and Nucleases as Antiproliferative Agens Targeting Human Tumors Growing in Mice
Recent Patents on DNA & Gene Sequences Current Targeting Strategies for Adenovirus Vectors in Cancer Gene Therapy
Current Cancer Drug Targets New Indications for Established Drugs: Combined Tumor-Stroma-Targeted Cancer Therapy with PPARγ Agonists, COX-2 Inhibitors, mTOR Antagonists and Metronomic Chemotherapy
Current Cancer Drug Targets Rediscovering Tocophersolan: A Renaissance for Nano-Based Drug Delivery and Nanotheranostic Applications
Current Drug Targets Epigenetic Regulation of Gene Expression as an Anticancer Drug Target
Current Cancer Drug Targets Too Much of a Good Thing: Suicide Prevention Promotes Chemoresistance in Ovarian Carcinoma
Current Cancer Drug Targets Functional Roles of the Ca2+-activated K+ Channel, KCa3.1, in Brain Tumors
Current Neuropharmacology Mammalian Target of Rapamycin (mTOR) Inhibitors as Anti-Cancer Agents
Current Cancer Drug Targets Glycomics: Relevance for Personalized Medicine
Current Pharmacogenomics and Personalized Medicine