Semisynthesis of natural flavones inhibiting tubulin polymerization, from hesperidin.
Semisynthesis of 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (1), a natural flavone that binds with high affinity to tubulin, was performed from hesperidin, the very abundant Citrus flavanone, by a five-step sequence. The last step of the synthesis also gave rise to 5,3'-dihydroxy-3,6,7,4'-tetramethoxyflavone (= casticin or vitexicarpin) (10), 5,3'-dihydroxy-3,7,8,4'-tetramethoxyflavone (= gossypetin 3,7,8,4'-tetramethyl ether) (11), and, unexpectedly, 5,7,3'-trihydroxy-3,6,8,4'-tetramethoxyflavone (12) and 5,3'-dihydroxy-8-dimethylamino-3,6,7,4'-tetramethoxyflavone (= 8-dimethylaminocasticin) (13). Cytotoxicity and antitubulin activity of these five flavones, as well as 5,3'-dihydroxy-3,7,4'-trimethoxyflavone (= ayanin) (14) and intermediate 6,8-dibromo-ayanin (8), were evaluated. Comparison of the responses confirmed and clarified the influence of the A-ring substitution pattern on the biological activity.
Lewin
Guy
G
Laboratoire de Pharmacognosie, Faculte de Pharmacie, Universite Paris-Sud 11 BIOCIS UMR-8076 CNRS, Avenue J.B. Clement, 92296 Chatenay-Malabry Cedex, France. guy.lewin@u-psud.fr
Maciuk
Alexandre
A
Thoret
Sylviane
S
Aubert
Geneviève
G
Dubois
Joëlle
J
Cresteil
Thierry
T
D002957:Citrus / Q000737:chemistry; D047309:Flavones / Q000737:chemistry / Q000378:metabolism; D005419:Flavonoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006569:Hesperidin / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C094782:5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone; D047309:Flavones; D005419:Flavonoids; D050257:Tubulin Modulators; D006569:Hesperidin; C059006:tangeretin