Synthesis and biochemical activities of antiproliferative amino acid and phosphate derivatives of microtubule-disrupting β-lactam combretastatins.

Abstract

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.

• Authors: Niamh M O'Boyle, Lisa M Greene, Niall O Keely, Shu Wang, Tadhg S Cotter, Daniela M Zisterer, Mary J Meegan
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 62 Pg. 705-21 (Apr 2013) ISSN: 1768-3254 [Electronic] France
• PMID: 23454513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amino Acids
• Antineoplastic Agents
• Phosphates
• Stilbenes
• fosbretabulin

Topics

• Amino Acids (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Humans
• MCF-7 Cells
• Microtubules (drug effects)
• Models, Molecular
• Molecular Structure
• Phosphates (chemical synthesis, chemistry, pharmacology)
• Solubility
• Stilbenes (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship