Guy Lewin

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.

Enhancement of the Water Solubility of Flavone Glycosides by Disruption of Molecular Planarity of the Aglycone Moiety

Enhancement of the water solubility by disruption of molecular planarity has recently been reviewed as a feasible approach in small-molecule drug discovery programs. We applied this strategy to some natural flavone glycosides, especially diosmin, a highly insoluble citroflavonoid prescribed as an oral phlebotropic drug. Disruption of planarity at the aglycone moiety by 3-bromination or chlorination afforded 3-bromo- and 3-chlorodiosmin, displaying a dramatic solubility increase compared with the parent compound.

Resolving the (19R) Absolute Configuration of Lanciferine, a Monoterpene Indole Alkaloid from Alstonia boulindaensis

Reinvestigation of the structure of lanciferine (1a) through extensive spectroscopic analysis in conjunction with a detailed computational study led to the unambiguous assignment of its (19 R) absolute configuration, thus leading to the full (2 R, 3 S, 7 S, 15 R, 16 R, 19 R, 20 S) assignment of lanciferine 45 years after its isolation.

Studies in the eburnane series: a new dimerization process

Abstract The behaviour of the synthetic (−)-16-(aminomethyl)eburnamenine (prepared from apovincamine) with formaldehyde was studied. Carrying out the reaction in acetic acid led to an original dimer, while in trifluoroacetic acid a 12-functionalized eburnamonine was isolated.