Conformational analysis of annonaceous acetogenins in liposomal membranes and mono-acylglycerides from the berries of Serenoa repens (saw-palmetto)
Abstract
Certain plant species belonging to the family Annonaceae produce Annonaceous acetogenins, which are a unique class of long-chain fatty acid derivatives with potent cytotoxicity. Putative targets of the acetogenins are membrane associated proteins including mitochondrial complex I. Asimicin, parviflorin, and longimicin B (compounds 1-3, respectively) belong to a class of Annonaceous acetogenins containing two tetrahydrofuran (THF) rings with hydrocarbon chains tethered to each ring; an $\alpha,\beta$-unsaturated $\gamma$-lactone ring is terminal to one of the alkyl chains. They differ in the alkyl chain length between the THF rings and the lactone ring. Annonacin (compound 5) is a mono-THF ring acetogenin and sylvaticin (compound 6) is a non-adjacent bis-THF ring acetogenin. The positions of the lactone and/or the THF rings of compounds 1-3, 5 and 6 within liposomal membranes were determined by proton ($\sp1$H) nuclear magnetic resonance spectroscopy. This is the first report elucidating the conformation of Annonaceous acetogenins in membranes. Solid state NMR studies of asimicin (1) in sn-2 chain perdeuterated dimyristoylphosphatidylcholine were undertaken to investigate the effects on membrane phase behavior, acyl chain ordering and head group conformation. It seems that 1 slows down the process of transition from the gel-state to the liquid-crystalline-state, but it does not disturb the molecular motions of phospholipids. A systematic set of isolated natural acetogenins was prepared and supplied to Dr. Hideto Miyoshi at Kyoto University for examination of their inhibitory actions with bovine heart mitochondrial complex I to identify the essential structural factors of these inhibitors for the exhibition of potent activity. Despite their very potent activity, the structural requirements of the acetogenins are not particularly rigid and remain somewhat ambiguous. The structure activity profile for complex I inhibition is discussed in comparison with those for other biological activities. In order to determine the mechanism of acetogenins, further experiments are indubitably required. Brine shrimp lethality-directed fractionation of the powdered, dried berries of Serenoa repens (Bart.) Small (saw-palmetto) (Palmae) led to the isolation of two monoacylglycerides, 1-monolaurin (25) and 1-monomyristin (26). Compounds 25 and 26 showed moderate biological activities. The fruits and extracts of saw-palmetto are taken orally as an herbal medicine to prevent prostatic hyperplasias.
Degree
Ph.D.
Advisors
McLaughlin, Purdue University.
Subject Area
Biochemistry|Organic chemistry|Cellular biology|Botany
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