5-3--dihydroxy-3-6-7-8-4--pentamethoxyflavone and tangeretin

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.

Topics: Citrus; Flavones; Flavonoids; Hesperidin; HL-60 Cells; Humans; Molecular Structure; Structure-Activity Relationship; Tubulin Modulators

A series of 3'-aminoflavones 5,6,7,8-tetra- or 5,7-dioxygenated on the A-ring was synthesized from tangeretin or naringin, two natural Citrus flavonoids. These flavones were evaluated for antiproliferative activity, activation of apoptosis, and inhibition of tubulin assembly. The most antiproliferative flavones exhibit a common 5-hydroxy-6,7,8-trimethoxy substitution pattern on the A-ring.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Flavanones; Flavones; Humans