Abstract
Paclitaxel is one of the most important anti-cancer agents introduced during the last 20 years. However, the use of paclitaxel is limited by undesirable side effects as well as the development of drug resistance. Here, we report a synthetic strategy towards spiro-bicyclo[2.2.2]octane derivatives, which includes double Michael addition and ring-closing metathesis as key synthetic steps. This strategy was used to synthesize a series of spiro-bicyclic compounds designed to be paclitaxel mimetics, which were evaluated in human breast-derived cell lines. One of these paclitaxel mimetics showed toxicity, although at higher concentrations than paclitaxel itself. In addition, two other spiro-bicyclic compounds, lacking the paclitaxel side chain, showed toxicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Breast / cytology
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Breast / drug effects*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / pathology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Female
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Humans
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MCF-7 Cells
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Molecular Conformation
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Molecular Mimicry
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Octanes / adverse effects
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Octanes / chemical synthesis
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Octanes / chemistry
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Octanes / pharmacology*
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Paclitaxel / adverse effects
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Paclitaxel / analogs & derivatives*
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Paclitaxel / chemical synthesis
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Paclitaxel / chemistry
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Paclitaxel / pharmacology*
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Spiro Compounds / adverse effects
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Octanes
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Spiro Compounds
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spirobicyclo(2.2.2)octane
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Paclitaxel