title: 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: School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland. oboyleni@tcd.ie
authors: Niamh M
authors: NM
authors: O'Boyle
authors: Lisa M
authors: LM
authors: Greene
authors: Niall O
authors: NO
authors: Keely
authors: Shu
authors: S
authors: Wang
authors: Tadhg S
authors: TS
authors: Cotter
authors: Daniela M
authors: DM
authors: Zisterer
authors: Mary J
authors: MJ
authors: Meegan
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D010710:Phosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D010710:Phosphates; D013267:Stilbenes; C058728:fosbretabulin