Abstract
Attention is increasingly being focussed on the cell cycle and apoptosis as potential targets for therapeutic intervention in cancer. Taking 1-[(2-oxepanyl)]-5-fluorouracil previously prepared by us, we committed ourselves to increase the lipophilicity of this upper cyclohomologue of Ftorafur and prepared a series of bioisosteric benzannelated seven-membered 5-FU O,N-acetals to test them against the MCF-7 human breast cancer cell line. Benzo-fused seven-membered O,O-acetals or their acyclic analogues led to the expected 5-FU O,N-acetals (or aminals), in addition to six- and to 14- membered aminal structures and acyclic compounds. All the cyclic aminals provoked a Go/G1-phase cell cycle arrest, whereas Ftorafur, a known prodrug of 5-FU, and 1-[2-(2-hydroxymethyl-4-nitrophenoxy)-1-methoxyethyl]-5-fluorouracil (51) induced an S-phase cell cycle arrest. Although breast cancer is most often treated with conventional cytotoxic agents it has proved difficult to induce apoptosis in breast cancer cells and, consequently, improved clinical responses may be obtained by identifying therapies that are particularly effective in activating apoptosis. 1-(2,3- Dihydrobenzoxepin-2-yl)-5-fluorouracil (26) may be particularly useful in stimulating apoptosis in breast cancer. This compound is more potent as an apoptotic inductor than paclitaxel (Taxol®). Finally, a fact that is worth emphasizing is that the cyclic and acyclic 5-FU O,N-acetals induce neither toxicity nor death in mice after one months treatment when administered intravenously twice a week, with a 50 mg/kg dose each time. Taken together, the experimental findings provide evidence of specific anti-tumour activity of these new substances and warrant further evaluation in in vivo models of breast cancer to future clinical applications.
Keywords: anti-tumour drugs, breast cancer, cell cycle, programmed cell death, 1-[3-(hydroxymethyl)-1,4-dioxepan-5-yl]pyrimidines, benzodioxepins, neighbouring group participation, lipophilicity
Current Medicinal Chemistry
Title: New Medium Oxacyclic O,N-Acetals and Related Open Analogues: Biological Activities
Volume: 12 Issue: 12
Author(s): Joaquin Campos, Estrella Saniger, Juan A. Marchal, Stefania Aiello, Ines Suarez, Houria Boulaiz, Antonia Aranega, Miguel A. Gallo and Antonio Espinosa
Affiliation:
Keywords: anti-tumour drugs, breast cancer, cell cycle, programmed cell death, 1-[3-(hydroxymethyl)-1,4-dioxepan-5-yl]pyrimidines, benzodioxepins, neighbouring group participation, lipophilicity
Abstract: Attention is increasingly being focussed on the cell cycle and apoptosis as potential targets for therapeutic intervention in cancer. Taking 1-[(2-oxepanyl)]-5-fluorouracil previously prepared by us, we committed ourselves to increase the lipophilicity of this upper cyclohomologue of Ftorafur and prepared a series of bioisosteric benzannelated seven-membered 5-FU O,N-acetals to test them against the MCF-7 human breast cancer cell line. Benzo-fused seven-membered O,O-acetals or their acyclic analogues led to the expected 5-FU O,N-acetals (or aminals), in addition to six- and to 14- membered aminal structures and acyclic compounds. All the cyclic aminals provoked a Go/G1-phase cell cycle arrest, whereas Ftorafur, a known prodrug of 5-FU, and 1-[2-(2-hydroxymethyl-4-nitrophenoxy)-1-methoxyethyl]-5-fluorouracil (51) induced an S-phase cell cycle arrest. Although breast cancer is most often treated with conventional cytotoxic agents it has proved difficult to induce apoptosis in breast cancer cells and, consequently, improved clinical responses may be obtained by identifying therapies that are particularly effective in activating apoptosis. 1-(2,3- Dihydrobenzoxepin-2-yl)-5-fluorouracil (26) may be particularly useful in stimulating apoptosis in breast cancer. This compound is more potent as an apoptotic inductor than paclitaxel (Taxol®). Finally, a fact that is worth emphasizing is that the cyclic and acyclic 5-FU O,N-acetals induce neither toxicity nor death in mice after one months treatment when administered intravenously twice a week, with a 50 mg/kg dose each time. Taken together, the experimental findings provide evidence of specific anti-tumour activity of these new substances and warrant further evaluation in in vivo models of breast cancer to future clinical applications.
Export Options
About this article
Cite this article as:
Campos Joaquin, Saniger Estrella, Marchal A. Juan, Aiello Stefania, Suarez Ines, Boulaiz Houria, Aranega Antonia, Gallo A. Miguel and Espinosa Antonio, New Medium Oxacyclic O,N-Acetals and Related Open Analogues: Biological Activities, Current Medicinal Chemistry 2005; 12 (12) . https://dx.doi.org/10.2174/0929867054020927
DOI https://dx.doi.org/10.2174/0929867054020927 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
Neuromodulators and Therapeutic Targets in Neuropathic Pain: From Molecules to Man
CNS & Neurological Disorders - Drug Targets Current and Emerging Systemic Therapy in Gastro-Esophageal Cancer “The Old and New Therapy for Metastatic Disease, The Role of Adjuvant and Neoadjuvant Therapy for Localized Disease”
Current Clinical Pharmacology Engineering Nanomedicines to Overcome Multidrug Resistance in Cancer Therapy
Current Medicinal Chemistry High-level Soluble Expression, Purification, and Functional Characterization of the Recombinant Human Leukemia Inhibitory Factor: A Potential General Strategy for the Recombinant Expression of Cytokines Consisting of Four α-Helices in a Bundle
Protein & Peptide Letters The Role of Endocytic Pathways on Estrogen Receptor α Intracellular Trafficking and 17β-estradiol Signaling
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Naturally Occurring Hydroxytyrosol: Synthesis and Anticancer Potential
Current Medicinal Chemistry A Review on Synthetic and Natural Steroid Dimers: 1997-2006
Current Medicinal Chemistry Updates of mTOR Inhibitors
Anti-Cancer Agents in Medicinal Chemistry CXCR4-CXCL12-Dependent Inflammatory Network and Endothelial Progenitors
Current Medicinal Chemistry Discovery and Development of Natural Products and their Derivatives as Photosensitizers for Photodynamic Therapy
Current Medicinal Chemistry Mechanisms of Action of Imidazoacridinone and Triazoloacridinone Derivatives in View of their Biological Activity
Current Pharmaceutical Analysis Using PET Studies of P-gp Function to Elucidate Mechanisms Underlying the Disposition of Drugs
Current Topics in Medicinal Chemistry Phytoestrogens in Postmenopause: The State of the Art from a Chemical, Pharmacological and Regulatory Perspective
Current Medicinal Chemistry The Anti-Proliferative Activity of Anisosciadone: A New Guaiane Sesquiterpene from Anisosciadium lanatum
Anti-Cancer Agents in Medicinal Chemistry Interactions of the Aryl Hydrocarbon Receptor with Inflammatory Mediators:Beyond CYP1A Regulation
Current Drug Metabolism Overview of Flaxseed Patent Applications for the Reduction of Cholesterol Levels
Recent Patents on Food, Nutrition & Agriculture Hypoxia Signaling and the Metastatic Phenotype
Current Molecular Medicine Diversity of Anticancer and Antimicrobial Compounds from Lichens and Lichen-derived Fungi: A Systematic Review (1985-2017)
Current Organic Chemistry The Role of HLA Promoters in Autoimmunity
Current Pharmaceutical Design VEGF Signal System: The Application of Antiangiogenesis
Current Medicinal Chemistry