Search

Three new monoterpene indole alkaloids (1–3) have been isolated from the bark of Geissospermum laeve, together with the known alkaloids (−)-leuconolam (4), geissolosimine (5), and geissospermine (6). The structures of 1–3were elucidated by analysis of their HRMS and NMR spectroscopic data. The absolute configuration of geissolaevine (1) was deduced from the comparison of experimental and theoretically calculated ECD spectra. The isolation workflow was guided by a molecular networking-based dereplication strategy using an in-house database of monoterpene indole alkaloids. In addition, five known compounds previously undescribed in the Geissospermumgenus were dereplicated from the G. laevealkaloid extract network and were assigned with various levels of identification confidence. The antiparasitic activities against Plasmodium falciparumand Leishmania donovanias well as the cytotoxic activity against the MRC-5 cell line were determined for compounds 1–5.

Dengue virus is the world's most prevalent human pathogenic arbovirus. There is currently no treatment or vaccine, and solutions are urgently needed. We previously demonstrated that biflavonoids from Dacrydium balansae, an endemic gymnosperm from New Caledonia, are potent inhibitors of the Dengue virus NS5 RNA-dependent RNA polymerase. Herein we describe the structure-activity relationship study of 23 compounds: biflavonoids from D. balansae (1-4) and from D. araucarioides (5-10), hexamethyl-amentoflavone (11), cupressuflavone (12), and apigenin derivatives (13-23). We conclude that 1) over the four different biflavonoid skeletons tested, amentoflavone (1) and robustaflavone (5) are the most promising ones for antidengue drug development, 2) the number and position of methyl groups on the biflavonoid moiety modulate their inhibition of Dengue virus NS5 RNA-dependent RNA polymerase, and 3) the degree of oxygenation of flavonoid monomers influences their antidengue potential. Sotetsuflavone (8), with an IC50 = 0.16 µM, is the most active compound of this series and is the strongest inhibitor of the Dengue virus NS5 RNA-dependent RNA polymerase described in the literature. [ABSTRACT FROM AUTHOR]

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.

Bioassay‐guided fractionation of the stem bark of Muntafara sessilifoliahas led to the isolation of six new vobasinyl‐iboga bisindole alkaloids, tabernaelegantinals A, B and E, and (3′R)‐hydroxytabernaelegantines A, C and D, together with six known monomeric indole and two bisindole alkaloids. The structures of these alkaloids were established by NMR and MS analysis. The bisindole alkaloids demonstrated cytotoxicity against the human lung MRC‐5 and rat skeletal muscle L‐6 cell lines whereas only one monomeric indole alkaloid was found to be cytotoxic. Tabernaemontanine acetate was found to be selectively antiplasmodial against the chloroquine‐resistant strain FcB1 of Plasmodium falciparum(5.3 μMIC50) over mammalian cell lines (selectivity index > 45). The tabernaelegantinals share an unprecedented α‐amino aldehyde moiety, the biosynthetic origin of which is discussed.

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 Citrusflavanone, 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.

A series of morphine and morphinan derivatives were chromatographed on a column containing immobilized cellular membranes from a cell line expressing the α3β4  neuronal nicotinic acetylcholine receptor (α3β4 nAChR).The results were analyzed using chemometric and molecular modeling techniques in order to predict the noncompetitive inhibitory (NCI) activity of these compounds, the molecular basis for the predicted activity and the binding sites of the inhibitors.The data demonstrated that seven of seven morphinans were NCIs and bound in the central lumen of the nAChR while only 2 of 13 morphine derivatives had NCI activity and these compounds most likely bound at the quinacrine binding site on the nAChR. The predicted activities were confirmed using functional inhibition studies.The results indicate that this approach can be used to rapidly assess pharmacological activity and to guide new drug design.