Ralf Mayer

Structure―activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP)

Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH(3) for the interaction with BCRP.

Flavonoids from Leptospermum scoparium

Abstract An investigation of L. scoparium afforded three new flavonoids. A previously mentioned triterpene diol appeared as a mixture of uvaol and betulinol.

Alkaloids from Hypecoum leptocarpum

Two new alkaloids, named isohyperectine and leptocarpine, were isolated from the whole plants of Hypecoum leptocarpum, along with the eight known alkaloids, dihydrosanguinarine, 8-acetonyldihydrosanguinarine, 8-methoxydihydrosanguinarine, oxohydrastinine, allocryptopine, protopine, hyperectine and corydamine. All structures were determined by spectroscopic methods.

Cucurbitacins from Wilbrandia ebracteata

Abstract Three new cucurbitacins were isolated from the roots of Wilbrandia ebracteata and their structures established as 16α, 23α-epoxy-2β,3β,20β-trihydroxy-10α,23β-cucurbit-5,24-dien-11-one, 16α,23α-epoxy-2β,3β,20β-trihydroxy- 10α,23α-cucurbit-5,24-dien-11-one and 2β,3β,16α,20,25-pentahydroxy-10α-cucurbit-5,23-dien-11-one, mainly by spectroscopy.

Triterpenoid glycosides from Stauntonia hexaphylla

On the basis of spectroscopic and chemical methods, the structures of two new bisdesmosidic triterpenoid glycosides, named staunoside D and E, which were isolated from Stauntonia hexaphylla, were established as 3-O-(beta-D-glucopyranosyl(1-->2)-[beta-D- glucopyranosyl(1-->3)]-beta-D-glucopyranosyl)-hederagenin-28- O-[beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranosyl] ester and 28-O-[alpha-L-rhamnopyranosyl (1-->4)-beta-D-glucopyranosyl(1-->6)-beta-D-glucopyranosyl]ester, respectively. Three known triterpenoid glycosides were also isolated. A new proglycoside was isolated from the cleavage of the ester-glycosidic linkage and its structure characterized.

A non-oxidized melampolide and other germacranolides from Aristolochia yunnanensis

Abstract Four sesquiterpene lactones have been isolated from the underground parts of Aristolochia yunnanensis growing in the Yunnan province of China. Three were identified as the known germacranolides costunolide, dehydrocostuslactone and α-cyclocostunolide. The structure of the fourth compound, the non-oxidized melampolide, was elucidated by spectroscopic methods and X-ray analysis.

Bisepoxylignan glycosides from Stauntonia hexaphylla

Abstract Three bisepoxylignan glycosides were isolated from Stauntonia hexaphylla . One is a new compound, (+)-1-hydroxysyringaresinol-1-β- d -glucoside named staunoside C, whilst the other two, (+)-fraxiresinol-1-β- d -glucoside and (+)-1-hydroxypinoresinol-1-β- d -glucoside, are reported in this genus for the first time. Structures were established on the basis of spectroscopic analysis and chemical evidence, and their 1 H NMR signals were assigned in detail by means of 2D-NMR techniques.

Oxidized aristolane sesquiterpenes from Aristolochia debilis

Abstract The underground parts of Aristolochia debilis have afforded three new aristolane type sesquiterpenes: 1(1O)-aristolenal-(15), 1α-hydroperoxy-1(10)aristolenone-(2); and 9α-hydroxy-9-aristolenone-(8).

Isobicyclogermacrenal from aristolochia manshuriensis

Abstract The previously unknown (+)-isobicyclogermacrenal was isolated from Aristolochia manshuriensis. Its structure was elucidated by spectroscopic means and X-ray analysis.

Allergenic sesquiterpene lactones from Eupatorium cannabinum L. and Kaunia rufescens (Lund ex de Candolle)

From Eupatorium cannabinum L., a hitherto unknown alpha-methylene-gamma-butyrolactone, 3 beta-peroxyeucannabinolide, was isolated. This compound and eupatoriopicrin from the same plant showed a weak sensitizing capacity in guinea pigs. 2-oxoludartin and dehydroleucodin, isolated from Kaunia rufescens (syn. Eupatorium rufescens), were strong sensitizers in the same sensitizarian procedure.