This item is available under a Creative Commons License for non-commercial use only
1. NATURAL SCIENCES, 1.4 CHEMICAL SCIENCES, Organic Chemistry, Biochemistry and molecular biology
The synthesis and biochemical activities of novel water-soluble β-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, β-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, β-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of tubulin in vitro. This indicates that the β-lactam amides did not require metabolic activation to have antiproliferative effects, in contrast to the phosphate series. Both series of compounds caused mitotic catastrophe and apoptosis in MCF-7 cells. Molecular modelling studies indicated potential binding conformations for the β-lactam amino acid amides 10k and 11l in the colchicine-binding site of tubulin. Due to their aqueous solubility and potent biochemical effects, these compounds are promising candidates for further development as microtubule-disrupting agents.
O'Boyle, N. et al (2013). Synthesis and biochemical activities of antiproliferative amino acid and phosphate derivatives of microtubule-disrupting beta-lactam combretastatins. European Journal of Medicinal Chemistry, 2013,62, pp. 705-721. DOI: http://dx.doi.org/10.1016/j.ejmech.2013.01.016
Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Heterocyclic Compounds Commons, Medicinal Chemistry and Pharmaceutics Commons, Organic Chemicals Commons, Other Chemicals and Drugs Commons, Pharmaceutical Preparations Commons