Abstract
Derivatives of the vitamin folic acid function in the body for the synthesis of thymidylate, purines and amino acids and are necessary for normal metabolism and growth. Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR) is the outstanding example of an antitumor antifolate. MTX is clinically useful in the treatment of childhood leukemia, choriocarcinoma and psoriasis, where it corrects abnormal growth, and in rheumatoid arthritis and other autoimmune diseases where it corrects abnormal immune function. Since 1949, when the chemical synthesis of MTX was reported by workers at the Lederle Laboratories of the American Cyanamid Company, much has been learned about the basis of antifolate cytotoxicity and selectivity. This review will focus on deaza antifolates which are: 1) presently under clinical development and 2) less developed compounds which represent novel approaches. Compounds will be grouped according to their enzyme targets; DHFR , thymidylate synthase (TS) and glycinamide ribonucleotide formyltransferase (GARFT). In addition to inhibition of target enzymes, antifolate membrane transport into cells and conversion to poly-L-γ-glutamate forms are important considerations in drug design along with the reverse processes, cellular hydrolysis of antifolate poly- L-γ-glutamates to monoglutamates and the extrusion of the monoglutamates through the cell membrane. These processes can be modulated by competition with folates.
Keywords: deaza analogs, folic acid, antitumor agents, dihydrofolate reductase, antitumor antifolate
Current Pharmaceutical Design
Title: Deaza Analogs of Folic Acid as Antitumor Agents
Volume: 9 Issue: 31
Author(s): R. L. Kisliuk
Affiliation:
Keywords: deaza analogs, folic acid, antitumor agents, dihydrofolate reductase, antitumor antifolate
Abstract: Derivatives of the vitamin folic acid function in the body for the synthesis of thymidylate, purines and amino acids and are necessary for normal metabolism and growth. Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR) is the outstanding example of an antitumor antifolate. MTX is clinically useful in the treatment of childhood leukemia, choriocarcinoma and psoriasis, where it corrects abnormal growth, and in rheumatoid arthritis and other autoimmune diseases where it corrects abnormal immune function. Since 1949, when the chemical synthesis of MTX was reported by workers at the Lederle Laboratories of the American Cyanamid Company, much has been learned about the basis of antifolate cytotoxicity and selectivity. This review will focus on deaza antifolates which are: 1) presently under clinical development and 2) less developed compounds which represent novel approaches. Compounds will be grouped according to their enzyme targets; DHFR , thymidylate synthase (TS) and glycinamide ribonucleotide formyltransferase (GARFT). In addition to inhibition of target enzymes, antifolate membrane transport into cells and conversion to poly-L-γ-glutamate forms are important considerations in drug design along with the reverse processes, cellular hydrolysis of antifolate poly- L-γ-glutamates to monoglutamates and the extrusion of the monoglutamates through the cell membrane. These processes can be modulated by competition with folates.
Export Options
About this article
Cite this article as:
Kisliuk L. R., Deaza Analogs of Folic Acid as Antitumor Agents, Current Pharmaceutical Design 2003; 9 (31) . https://dx.doi.org/10.2174/1381612033453695
DOI https://dx.doi.org/10.2174/1381612033453695 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
- Announcements
Related Articles
-
The Carnitine Transporter Network: Interactions with Drugs
Current Chemical Biology Advances of Phenoxazines: Synthesis, Reactivity and Their Medicinal Applications
Current Medicinal Chemistry An overview of ABC and SLC Drug Transporter Gene Regulation
Current Drug Metabolism Gestational Trophoblastic Neoplasia, an Ancient Disease: New Light and Potential Therapeutic Targets
Anti-Cancer Agents in Medicinal Chemistry Hypoxic Culture Conditions for Mesenchymal Stromal/Stem Cells from Wharton’s Jelly: A Critical Parameter to Consider in a Therapeutic Context
Current Stem Cell Research & Therapy Kinetic Evaluation of Anti-tumor Chlorambucil Release from O-stearoyl Mannose PLGA Nanoparticles
Current Nanomedicine MicroRNA Polymorphisms, MicroRNA Pharmacogenomics and Cancer Susceptibility
Current Pharmacogenomics and Personalized Medicine Importance of Wnt Signaling in the Tumor Stroma Microenvironment
Current Cancer Drug Targets Transcriptional Control of Collagen I Gene Expression
Cardiovascular & Hematological Disorders-Drug Targets The Role of Trophoblast Nutrient and Ion Transporters in the Development of Pregnancy Complications and Adult Disease
Current Vascular Pharmacology Assessing Drug Transport Across the Human Placental Barrier: From In Vivo and In Vitro Measurements to the Ex Vivo Perfusion Method and In silico Techniques
Current Pharmaceutical Biotechnology Functional Role of miR-34 Family in Human Cancer
Current Drug Targets Impact of Curcumin on Microsomal Enzyme Activities: Drug Interaction and Chemopreventive Studies
Current Medicinal Chemistry Gynecomastia in Infants, Children, and Adolescents
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Fungal Proteins with Antiproliferative and Anticancer Activities
Protein & Peptide Letters Unravelling the Role of Infectious Agents in the Pathogenesis of Human Autoimmunity: The Hypothesis of the Retroviral Involvement Revisited
Current Molecular Medicine Toxicology of Tributyltin in Mammalian Animal Models
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Targeted Therapies in Breast Cancer: Established Drugs and Recent Developments
Current Clinical Pharmacology An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs
Current Topics in Medicinal Chemistry Recent Patents on Alphavirus Protein Expression and Vector Production
Recent Patents on Biotechnology