4-hydroxy-n-desmethyltamoxifen and combretastatin

Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound

Topics: Antineoplastic Agents, Phytogenic; Bibenzyls; Cell Proliferation; Crystallography, X-Ray; Cyclofenil; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; Humans; Inhibitory Concentration 50; Leukocytes, Mononuclear; Ligands; MCF-7 Cells; Models, Molecular; Molecular Conformation; Protein Binding; Receptors, Estrogen; Tamoxifen