Synthesis and biological evaluation of polymethoxylated 4-heteroarylcoumarins as tubulin assembly inhibitor.
A series of syn-restricted polymethoxylated 4-heteroarylcoumarins--the isostuctural analogs of combretastatin A-4--was synthesized by Suzuki-Miyaura cross-coupling reaction and evaluated for antiproliferative activity. The 4-(1-methyl-1H-indol-5-yl)chromen-2-ones exhibit a potent cytotoxicity against HBL100 epithelial cell line with an IC(50) value amounting to 0.098 and 0.078 microM, respectively. The two compounds, having an indolyl moiety, potent inhibit in vitro microtubule assembly with a substoichiometric mode of action. A structure-activity relationship was discussed and the indolyl moiety was proved to be a good surrogate for the 3-hydroxy-4-methoxyphenyl ring of CA-4.
Ganina
Olga G
OG
Department of Chemistry, Moscow State Lomonosov University, Vorobyevy Gory, 119992 Moscow, Russia.
Daras
Etienne
E
Bourgarel-Rey
Véronique
V
Peyrot
Vincent
V
Andresyuk
Alexey N
AN
Finet
Jean-Pierre
JP
Fedorov
Alexey Yu
AY
Beletskaya
Irina P
IP
Combes
Sébastien
S
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D013267:Stilbenes / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D003374:Coumarins; D003432:Cross-Linking Reagents; D013267:Stilbenes; D050257:Tubulin Modulators; C058728:fosbretabulin