Abstract
The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, β-Dglucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a β-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)- bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.
Keywords: Oxazaphosphorine, cyclophosphamide, ifosfamide, trofosfamide, glufosfamide, mafosfamide
Current Pharmaceutical Design
Title: Design of New Oxazaphosphorine Anticancer Drugs
Volume: 13 Issue: 9
Author(s): Jun Liang, Min Huang, Wei Duan, Xue-Qing Yu and Shufeng Zhou
Affiliation:
Keywords: Oxazaphosphorine, cyclophosphamide, ifosfamide, trofosfamide, glufosfamide, mafosfamide
Abstract: The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, β-Dglucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a β-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)- bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.
Export Options
About this article
Cite this article as:
Liang Jun, Huang Min, Duan Wei, Yu Xue-Qing and Zhou Shufeng, Design of New Oxazaphosphorine Anticancer Drugs, Current Pharmaceutical Design 2007; 13 (9) . https://dx.doi.org/10.2174/138161207780414296
DOI https://dx.doi.org/10.2174/138161207780414296 |
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
-
Prevalence and Resistance Profiles of Vancomycin-resistant Enterococcal Isolates in Iran; An Eight-month Report from Nine Major Cities
Infectious Disorders - Drug Targets Antifungal Drug Discovery through the Study of Invertebrate Model Hosts
Current Medicinal Chemistry In-Vivo Gene Delivery by Sonoporation: Recent Progress and Prospects
Current Gene Therapy Design and Optimization of Itraconazole Loaded SLN for Intranasal Administration Using Central Composite Design
Nanoscience & Nanotechnology-Asia Effect of Administration Route on the Biodistribution and Shedding of Replication-Deficient AAV2: A Qualitative Modelling Approach
Current Gene Therapy In-silico Subtractive Proteomic Analysis Approach for Therapeutic Targets in MDR Salmonella enterica subsp. enterica serovar Typhi str. CT18
Current Topics in Medicinal Chemistry Nanomedicines for Brain Targeting: A Patent Review
Recent Patents on Nanomedicine Therapeutic Potential of Targeting TREM-1 in Inflammatory Diseases and Cancer
Current Pharmaceutical Design Tuberculosis - Present Medication and Therapeutic Prospects
Current Medicinal Chemistry Repurposing Ruxolitinib in Combating COVID-19: A Mini-review
New Emirates Medical Journal Anti-Infective Strategies of the Future: Is there Room for Species-Specific Antibacterial Agents?
Current Pharmaceutical Design Cerebrovascular Amyloidosis and Dementia
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Ecological Infectomics (Ecoinfectomics): Symbiotic Solutions to Microbial Infections
Anti-Infective Agents Caring for HIV-Infected Patients in the ICU in The Highly Active Antiretroviral Therapy Era
Current HIV Research Recent Patents on Stem Cell-Mediated Cartilage Regeneration and Repair
Recent Patents on Regenerative Medicine Human Anthrax as a Re-Emerging Disease
Recent Patents on Anti-Infective Drug Discovery Plant and Animal Steroids a New Hope to Search for Antiviral Agents
Current Medicinal Chemistry Aerosol Delivery in the Treatment of Lung Cancer
Current Cancer Drug Targets Intrathecal Enzyme Replacement Therapy for Mucopolysaccharidosis I: Translating Success in Animal Models to Patients
Current Pharmaceutical Biotechnology Progression of Alzheimer-type Neurofibrillary Tangles is Related to the Proximodistal Segments of the Hemispheric Arteries
Current Alzheimer Research