Abstract
Selective estrogen receptor modulators (SERMs) such as tamoxifen and toremifene are clinically useful drugs in the endocrine treatment of estrogen receptor positive breast cancer while raloxifene is an effective intervention for osteoporosis. In an ongoing SERM discovery programme we now report the synthesis of a series of 3-benzyl-4,6-diarylhex- 3-enes and 3,4,6-triarylhex-3-enes containing an extended flexible core structure. In these novel structures, the ethylene group acts as a flexible spacing group linking the aryl Ring A or Ring B with the core alkene group. In the benzyl-4,6- diarylhex-3-ene series an additional methylene group is inserted as a spacing group between the aryl ring C and the ethylene core group. These products demonstrated antiproliferative activity against the MCF-7 human breast cancer cell line. The alkene compounds were also shown to have binding affinity for the estrogen receptor alpha (IC50 values for the most active compounds in the range 0.110-0.293?M) together with selectivity for ER / . The compounds demonstrated antiestrogenic activity in Ishikawa cells with low estrogenic stimulation. The structure-activity relationships for the active ligands were further explored in a computational study where docked structures of the active compounds were compared with the X-ray crystal structures for the complexes of ER with 4-hydroxytamoxifen and ER with raloxifene. The alignment of the aromatic rings B and C of the compounds within the ligand binding domain could then be correlated with their observed ER / selectivity.
Keywords: Estrogen receptor modulators, 3-benzyl-4,6-diarylhex-3-ene, 3,4,6-triarylhex-3-ene, antiestrogens, anticancer
Medicinal Chemistry
Title: Flexible Estrogen Receptor Modulators: Synthesis, Biochemistry and Molecular Modeling Studies for 3-Benzyl-4,6-diarylhex-3-ene and 3,4,6-Triarylhex-3-ene Derivatives
Volume: 3 Issue: 2
Author(s): Helena M. Smith, Andrew J. S. Knox, Daniela M. Zisterer, David G. Lloyd and Mary J. Meegan
Affiliation:
Keywords: Estrogen receptor modulators, 3-benzyl-4,6-diarylhex-3-ene, 3,4,6-triarylhex-3-ene, antiestrogens, anticancer
Abstract: Selective estrogen receptor modulators (SERMs) such as tamoxifen and toremifene are clinically useful drugs in the endocrine treatment of estrogen receptor positive breast cancer while raloxifene is an effective intervention for osteoporosis. In an ongoing SERM discovery programme we now report the synthesis of a series of 3-benzyl-4,6-diarylhex- 3-enes and 3,4,6-triarylhex-3-enes containing an extended flexible core structure. In these novel structures, the ethylene group acts as a flexible spacing group linking the aryl Ring A or Ring B with the core alkene group. In the benzyl-4,6- diarylhex-3-ene series an additional methylene group is inserted as a spacing group between the aryl ring C and the ethylene core group. These products demonstrated antiproliferative activity against the MCF-7 human breast cancer cell line. The alkene compounds were also shown to have binding affinity for the estrogen receptor alpha (IC50 values for the most active compounds in the range 0.110-0.293?M) together with selectivity for ER / . The compounds demonstrated antiestrogenic activity in Ishikawa cells with low estrogenic stimulation. The structure-activity relationships for the active ligands were further explored in a computational study where docked structures of the active compounds were compared with the X-ray crystal structures for the complexes of ER with 4-hydroxytamoxifen and ER with raloxifene. The alignment of the aromatic rings B and C of the compounds within the ligand binding domain could then be correlated with their observed ER / selectivity.
Export Options
About this article
Cite this article as:
Smith M. Helena, S. Knox J. Andrew, Zisterer M. Daniela, Lloyd G. David and Meegan J. Mary, Flexible Estrogen Receptor Modulators: Synthesis, Biochemistry and Molecular Modeling Studies for 3-Benzyl-4,6-diarylhex-3-ene and 3,4,6-Triarylhex-3-ene Derivatives, Medicinal Chemistry 2007; 3 (2) . https://dx.doi.org/10.2174/157340607780059503
DOI https://dx.doi.org/10.2174/157340607780059503 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...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
-
Irradiation Toxicity and Inflammatory Bowel Diseases (IBD): Review
Reviews on Recent Clinical Trials Targeting the Kinetochore in Cancer Therapy: The Ndc80/Hec1 Complex
Current Drug Therapy Development of Small Molecule Non-peptide Formyl Peptide Receptor (FPR) Ligands and Molecular Modeling of Their Recognition
Current Medicinal Chemistry Evaluation of Novel Radioiodinated C7-substituted Δ6,7 – estradiol Derivatives for Molecular Recognition of ER-Positive Breast Tumours
Current Radiopharmaceuticals Mesothelioma - Update on Management
Current Respiratory Medicine Reviews Treating Dyslipidemias: Is Inflammation the Missing Link?
Medicinal Chemistry Wnt Signaling in Rhabdomyosarcoma – A Potential Targeted Therapy Option
Current Drug Targets Potential Anti-cancer Drugs Commonly Used for Other Indications
Current Cancer Drug Targets Combining Drug-Loaded Nanobubbles and Extracorporeal Shock Waves for Difficult-to-Treat Cancers
Current Drug Delivery Patents on Immunotoxins and Chimeric Toxins for the Treatment of Cancer
Recent Patents on Drug Delivery & Formulation Gonioprobe, an Innovative Gamma-probe to Guide Parathyroid Radioguided Surgery: First Clinical Experiences with Navigator and Lock-ontarget Functions
Current Radiopharmaceuticals A New Class of Coumate Benzimidazole Hybrids as BRCA 1 Mimetics Through Unconventional Binding Mode; Synthesis and Preliminary Cytotoxicity Screening
Current Computer-Aided Drug Design Progress in Evaluation of Pathologic Response to Neoadjuvant Chemotherapy of Breast Cancer
Anti-Cancer Agents in Medicinal Chemistry Multiple Mechanisms of Cytokine Action in Neurodegenerative and Psychiatric States: Neurochemical and Molecular Substrates
Current Pharmaceutical Design Potential Uses of MicroRNA in Lung Cancer Diagnosis, Prognosis, and Therapy
Current Cancer Drug Targets Nonprofit Pharma: Solutions to What Ails the Industry
Current Medicinal Chemistry Epigenetic Targets and their Inhibitors in Cancer Therapy
Current Topics in Medicinal Chemistry Aromatase, Estrogens and Testicular Germ Cell Development
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Pharmacological Control of Autophagy: Therapeutic Perspectives in Inflammatory Bowel Disease and Colorectal Cancer
Current Pharmaceutical Design The Interactions of Anticancer Agents with Tea Catechins: Current Evidence from Preclinical Studies
Anti-Cancer Agents in Medicinal Chemistry