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The low-energy collision-induced dissociation of protonated flavonoid O-diglycosides, i.e., flavonoid O-rutinosides and O-neohesperidosides, containing different aglycone types has been studied. The results indicate that the unusual [M + H - 162]+ ion formed by internal glucose residue loss, which in a previous study was shown to be a rearrangement ion, is strongly dependent upon the aglycone type. For 7-O-diglycosides, the internal glucose loss is very pronounced for aglycones of the flavanone type, but is completely absent for aglycones of the flavone and flavonol types. Internal glucose residue loss was found to correspond to a minor fragmentation pathway for flavonol 3-O-diglycosides. A plausible mechanism is proposed based on proton mobilization from the aglycone to the disaccharidic part of the flavonoid O-diglycosides which is supported by theoretical calculations and model building.

On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of beta-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of beta-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC(50) value against chloroquine-resistant P. falciparum of 4.0 microM in the absence of cytotoxicity (IC(50) > 32 microM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC(50) = 2.0 microM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity.

Tandem mass spectrometric methods have been evaluated for the characterisation of the type and the differentiation of the interglycosidic linkage of isomeric flavonoid O-diglycosides. Based on the occurrence of internal monosaccharide residue loss and the relative abundances of Y-type ions formed by fragmentation at glycosidic bonds, four pairs of isomeric flavonoid O-diglycosides can be unambiguously differentiated. The different techniques used, i.e. linked scanning at constant B/E without collisional activation and low-energy collision-induced dissociation using methane or helium as collision gas, have been shown to be useful for distinguishing the two most common (1, 2- and 1, 6-) interglycosidic linkages, e.g. flavonoid O-neohesperidosides and O-rutinosides.

Morinda morindoides (Baker) Milne-Redhead (syn. Gaertnera morindoides Bak.) is one of the most popular medicinal plants in the Democratic Republic of Congo. In relation to its traditional use against rheumatic pains, fractionation of both the EtOAc- and the n-BuOH-soluble fraction of the 80% MeOH extract of the leaves, guided by the anticomplementary activity on the classical activation pathway, yielded eight novel iridoids (1-8), all containing a spirolactone functionality. Their structure was elucidated using spectroscopic methods. Gaertneroside 1, acetylgaertneroside 2, and gaertneric acid 5 were found to inhibit the activation of the classical pathway of the complement system, with IC(50) values between 58 and 69 microM. In addition to the biologically active flavonoids reported before from the same plant, these complement-inhibiting iridoids may contribute at least in part to the traditional use against rheumatic pains.

The present study deals with the use of liquid secondary ion mass spectrometry in combination with collisionally activated dissociation and linked scanning at constant BIE for differentiation and structural analysis of 6-C-and 8-C-glycosidic flavonoids in the positive ion mode. Flavonoids of mono-C-glycosidic nature were investigated. Special emphasis is given to the rationalization of fragment ions which allow differentiation between isomers.

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