Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: synthesis and biological evaluation of antivascular activity.
The alpha-methyl chalcone SD400 is a potent inhibitor of tubulin assembly and possesses potent anticancer activity. Various chalcone analogues were synthesized and evaluated for their cell growth inhibitory properties against the K562 human chronic myelogenous leukemia cell line (SD400, IC(50) 0.21nM; combretastatin A4 CA4, IC(50) 2.0nM). Cell cycle analysis by flow cytometry indicated that these agents are antimitotic (SD400, 83% of the cells are in G(2)/M phase; CA4 90%). They inhibit tubulin assembly at low concentration (SD400, IC(50) 0.46microM; CA4, 0.10microM) and compete with [(3)H]colchicine for binding to tubulin (8% [(3)H]colchicine remained bound to tubulin after competition with SD400 or CA4). Upon treatment with SD400, remarkable cell shape changes were elicited in HUVEC cells, consistent with vasculature damaging activity.
Ducki
Sylvie
S
Department of Chemistry, UMIST, Manchester M60 1QD, UK. Sylvie.DUCKI@univ-bpclermont.fr
Rennison
David
D
Woo
Meiko
M
Kendall
Alexander
A
Chabert
Jérémie Fournier Dit
JF
McGown
Alan T
AT
Lawrence
Nicholas J
NJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D001632:Bibenzyls; D047188:Chalcones; D050257:Tubulin Modulators; C040105:combretastatin