Abstract
The goal of cancer chemotherapy with classical drugs – the destruction of the tumor cells – is often complicated by significant toxicity. As an alternative, induced differentiation modulates the cell programme by transforming malignant cells into mature cells with no proliferative potential. Our data demonstrate that (+/-)-1-{[3-(2-hydroxyethoxy)-1- isopropoxy]propyl}-5-fluorouracil inhibits proliferation, induces myogenic differentiation, increases the expression of proteins specifically present in normally differentiated skeletal muscle cells, and modifies the adhesion capacity of these cells against the rhabdomyosarcoma cell line RD. From a designing point of view, a benzene ring was fused to the side chain in order to increase the lipophilicity and anticancer activity of our molecules. Herein we report the preparation and biological activity of three compounds having the general formula (+/-)-1-[2-(5-substituted-2-hydroxybenzyloxy)-1- methoxyethyl]-5-fluorouracils. A catechol-derived compound such as (+/-)-1-[3-(2-hydroxyphenoxy)-1-methoxypropyl]- 5-fluorouracil and two salicyl-derived compounds such as (+/-)-(Z)-1-[4-(2-hydroxyphenyl)-1-methoxy-but-3-enyl]-5- fluorouracil [(Z)-43] and its dihydrogenated derivative (+/-)-1-[4-(2-hydroxyphenyl)-1-methoxybutyl]-5-fluorouracil were prepared to complete the set of six O,N-acetals. The most active compound against the MCF-7 breast cancer cell line was (+/-)-(Z)-43 with an IC50 = 9.40 ± 0.64 μM. Differentiated breast cancer cells generate fat deposits within the cytoplasm. The MCF-7 cells treated with (+/-)-(Z)-43 caused an increase in the lipid content over control cells after 3 days of treatment. Our results suggest that there may be significant potential advantages in the use of this new differentiating agent for the treatment of breast cancer.
Keywords: Acyclic O, N-acetals, acyclonucleosides, breast cancer, cellular differentiation, 5-fluorouracil
Current Medicinal Chemistry
Title: Acyclonucleosides, Modified Seco-Nucleosides, and Salicyl- or Catechol- Derived Acyclic 5-Fluorouracil O,N-Acetals: Antiproliferative Activities, Cellular Differentiation and Apoptosis
Volume: 16 Issue: 9
Author(s): Juan A. Marchal, Maria C. Nunez, Antonia Aranega, Miguel A. Gallo, Antonio Espinosa and Joaquin M. Campos
Affiliation:
Keywords: Acyclic O, N-acetals, acyclonucleosides, breast cancer, cellular differentiation, 5-fluorouracil
Abstract: The goal of cancer chemotherapy with classical drugs – the destruction of the tumor cells – is often complicated by significant toxicity. As an alternative, induced differentiation modulates the cell programme by transforming malignant cells into mature cells with no proliferative potential. Our data demonstrate that (+/-)-1-{[3-(2-hydroxyethoxy)-1- isopropoxy]propyl}-5-fluorouracil inhibits proliferation, induces myogenic differentiation, increases the expression of proteins specifically present in normally differentiated skeletal muscle cells, and modifies the adhesion capacity of these cells against the rhabdomyosarcoma cell line RD. From a designing point of view, a benzene ring was fused to the side chain in order to increase the lipophilicity and anticancer activity of our molecules. Herein we report the preparation and biological activity of three compounds having the general formula (+/-)-1-[2-(5-substituted-2-hydroxybenzyloxy)-1- methoxyethyl]-5-fluorouracils. A catechol-derived compound such as (+/-)-1-[3-(2-hydroxyphenoxy)-1-methoxypropyl]- 5-fluorouracil and two salicyl-derived compounds such as (+/-)-(Z)-1-[4-(2-hydroxyphenyl)-1-methoxy-but-3-enyl]-5- fluorouracil [(Z)-43] and its dihydrogenated derivative (+/-)-1-[4-(2-hydroxyphenyl)-1-methoxybutyl]-5-fluorouracil were prepared to complete the set of six O,N-acetals. The most active compound against the MCF-7 breast cancer cell line was (+/-)-(Z)-43 with an IC50 = 9.40 ± 0.64 μM. Differentiated breast cancer cells generate fat deposits within the cytoplasm. The MCF-7 cells treated with (+/-)-(Z)-43 caused an increase in the lipid content over control cells after 3 days of treatment. Our results suggest that there may be significant potential advantages in the use of this new differentiating agent for the treatment of breast cancer.
Export Options
About this article
Cite this article as:
Marchal A. Juan, Nunez C. Maria, Aranega Antonia, Gallo A. Miguel, Espinosa Antonio and Campos M. Joaquin, Acyclonucleosides, Modified Seco-Nucleosides, and Salicyl- or Catechol- Derived Acyclic 5-Fluorouracil O,N-Acetals: Antiproliferative Activities, Cellular Differentiation and Apoptosis, Current Medicinal Chemistry 2009; 16 (9) . https://dx.doi.org/10.2174/092986709787581824
DOI https://dx.doi.org/10.2174/092986709787581824 |
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
-
Understanding Mesenchymal Cancer: The Liposarcoma-Associated t(12;16) (q13;;p11) Chromosomal Translocation as a Model
Current Genomics TRP Channels and Cancer: New Targets for Diagnosis and Chemotherapy
Endocrine, Metabolic & Immune Disorders - Drug Targets Ion Channels as Medicinal Targets of Biological Toxins: The Impact of Automated Patch-Clamp Electrophysiology
Current Topics in Medicinal Chemistry Peptides or Small Molecules? Different Approaches to Develop More Effective CDK Inhibitors
Current Medicinal Chemistry Differentiation-Inducing Therapy for Solid Tumors
Current Pharmaceutical Design Inhibitory Role of Resveratrol in the Development of Profibrogenesis and Fibrosis Mechanisms
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Anti-Cancer Therapy: Targeting the Mevalonate Pathway
Current Cancer Drug Targets Computed Tomography (CT) Features of Pelvic Rhabdomyosarcoma (RMS) in Children
Current Medical Imaging VEGF Inhibitors in Cancer Therapy
Current Pharmaceutical Design Targeting MET Receptor in Rhabdomyosarcoma: Rationale and Progress
Current Drug Targets mTOR Inhibition and the Tumor Vasculature
Current Angiogenesis (Discontinued) Interactions of Chemicals and Metal Ions with Proteins and Role for Immune Responses
Mini-Reviews in Medicinal Chemistry Histotype in Non-Small Cell Lung Cancer Therapy and Staging: The Emerging Role of an Old and Underrated Factor
Current Respiratory Medicine Reviews Crocins: The Active Constituents of Crocus Sativus L. Stigmas, Exert Significant Cytotoxicity on Tumor Cells In Vitro
Current Cancer Therapy Reviews Inhibition of Polo-Like Kinase 1 by BI2536 Reverses the Multidrug Resistance of Human Hepatoma Cells In Vitro and In Vivo
Anti-Cancer Agents in Medicinal Chemistry Anti-Apoptotic Actions of Insulin-Like Growth Factors: Lessons from Development and Implications in Neoplastic Cell Transformation
Current Pharmaceutical Design Integrins: Regulators of Tissue Function and Cancer Progression
Current Pharmaceutical Design CD95 Signaling in Cancer Treatment
Current Pharmaceutical Design Heparanase as a Target in Cancer Therapy
Current Cancer Drug Targets Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins
Recent Patents on Anti-Cancer Drug Discovery