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Semisynthesis and pharmacological investigation of lipo-alkaloids prepared from aconitine by transesterification with eicosanoic acid analogues
Previously we reported the semisynthesis of 9 aconitine-derived lipo-alkaloids transesterified with fatty acids differing in the number of carbon atoms and double bonds in their chains . When these compounds were tested for COX-1, COX-2 and LTB4 formation inhibitory activities it was found that 14-benzoylaconine-8-O-eicosapentaenoate exhibited notable activities through all three in vitro anti-inflammatory test systems (inhibition (%): COX-1: 54.51, COX-2: 66.07, LTB4: 45.96, at 50µM concentration). Although no data exist on the natural occurrence of aconitine derived lipo-alkaloids containing eicosanoic acid analogues at C-8, the prospective of further charting the possible structure-activity relationships of lipo-alkaloids is reinforced by papers dealing with the importance and natural roles of different unsaturated eicosanoic acid derivatives in the process of inflammation . The present paper reports the semisynthesis of 7 eicosanoate analogues of aconitine-derived lipo-alkaloids, prepared according to the modified method of Bai et al . In the reactions, aconitine was transesterified by eicosanoic, 11-eicosenoic, 8,11,14-eicosatrienoic, 11,14,17-eicosatrienoic, 8,11,14,17-eicosatetraenoic and 5,8,11,14,17-eicosapentaenoic acids resulting the corresponding 14-benzoylaconin-8-O-esters and pyroaconitine. The reaction mixtures were purified of necessity by gelfiltration, preparative TLC and centrifugal planar chromatography. Purity of the obtained lipo-alkaloids was proved with the aid of NMR spectroscopy. The COX-1, COX-2 and LTB4 formation inhibitory activities of this eicosanoate lipo-alkaloid series were also investigated. It was observed that the 14-benzoylaconine-8-O-eicosapentaenoate has the highest activities (inhibition (%): COX-1: 82.84, COX-2: 33.67, at 50µM concentration) between the eicosanoate analogues.
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