Design and pharmacophore modeling of biaryl methyl eugenol analogs as breast cancer invasion inhibitors

• Published in: Bioorganic & medicinal chemistry 2010-01, Vol.18 (2), p.496-507
• Main Authors: Abdel Bar, Fatma M., Khanfar, Mohammad A., Elnagar, Ahmed Y., Badria, Farid A., Zaghloul, Ahmed M., Ahmad, Kadria F., Sylvester, Paul W., El Sayed, Khalid A.
• Format: Article
• Language: English
• Subjects: Anti-invasive; Antineoplastic agents; Biaryl; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Movement - drug effects; Computer Simulation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Eugenol - analogs & derivatives; Eugenol - chemistry; Eugenol - pharmacology; Female; General aspects; Heck and Suzuki coupling reactions; Humans; Medical sciences; Methyl eugenol; Microtubules; Models, Chemical; Models, Molecular; Neoplasm Invasiveness - prevention & control; Pharmacology. Drug treatments; Pharmacophore modeling; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2009.12.019

Cell invasion and migration are required for the parent solid tumor cells to metastasize to distant organs. Microtubules form a polarized network, enabling organelle and protein movement throughout the cell. Cytoskeletal elements coordinately regulate cell’s motility, adhesion, migration, exocytosis, endocytosis, and division. Thus, microtubule disruption can be a useful target to control cancer cell invasion and metastasis. The phenolic ether methyl eugenol ( 1), the major component of the essential oil of the leaves of Melaleuca ericifolia Sm. (Myrtaceae), was used as a starting scaffold to design eleven new and three known anti-tubulin agents 2– 15 using carbon–carbon coupling reactions. A computer-assisted approach was used to design these new biaryl derivatives using colchicine-binding site of tubulin as the molecular target and colchicine as an active ligand. Several derivatives showed potent inhibitory activity against MDA-MB-231 cell migration at the 1–4 μM dose range. The Z isomers, 4 and 15 were more active as invasion inhibitors compared to their structurally related E isomers, 2 and 14. The cytotoxic activities of compounds 2– 15 against two breast cancer cell lines MDA-MB-231 and MCF-7 were evaluated. Anti-invasive activity of the semisynthetic derivatives is not due to a direct cytotoxic effect on MDA-MB-231. Analogs 2– 15 may promote their anti-invasive activity through the induction of changes in cell morphology. A pharmacophore model was generated involving seven essential features for activity, which was consistent with a previously generated colchicine site inhibitors model.