Semisynthesis of Natural Flavones Inhibiting Tubulin Polymerization, from Hesperidin

Abstract

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.

Antivascular and anti-parasite activities of natural and hemisynthetic flavonoids from New Caledonian Gardenia species (Rubiaceae)

“…Our work once again demonstrates the importance of natural products as a source of leader compounds for antiangiogenesis or vascular disruption [28,29,34,35]. It is noteworthy that this series of naturally occurring compounds should be regarded as a model for future development and as valuable starting materials for pharmacomodulation.…”

“…Nevertheless, this ability to inhibit tubulin polymerization has already been observed in the case of flavones with a 5,7-dihydroxy-6,8-dimethoxyl pattern on the A ring and a 3 0 -hydroxy-4 0 -methoxy or 3 0 -amino-4 0 -methoxy substituted B ring [29,35]. A too bulky substitution on the B ring seems to lead to a slight decrease of ITP as observed in the case of flavones isolated from G. urvillei and G. oudiepe, exemplified by a 3 0 -hydroxy-4 0 ,5 0 -dimethoxyl 2 or 3 0 ,4 0 ,5 0 -trimethoxyl substitution 3 [28].…”

Cytotoxicity of Vitex agnus-castus fruit extract and its major component, casticin, correlates with differentiation status in leukemia cell lines

“…Then, the residue was further purified by recrystallization from n-hexane-EtOAc (3:1) to afford casticin as pale yellow crystals. mp 185-188˚C (n-hexane-EtOAc); 1 (17).…”

Synthesis of 6‐ or 8‐Bromo Flavonoids by Regioselective Mono‐Bromination and Deprotection Protocol from Flavonoid Alkyl Ethers

“…However, the strong acidic conditions limited their applications. In 2010 and 2014, Lewin and Rocco reported the bromination of quercetin and its derivatives with N ‐bromosuccinimide (NBS), respectively. However, a mixture of 6‐bromo, 8‐bromo, and 6,8‐dibromo products was obtained under these conditions.…”