71(P-53) 天然物由来の抗マラリア活性物質の探索研究(ポスター発表の部)

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• During the course of our program aiming at new antimalarials from natural resources, we found the methyl esters (1, 2) of peroxyplakoric acids A_3 and B_3 from a marine sponge of Plakortis sp. as active principles. In order to elucidate structural requirement for antimalarial activity of these peroxides, we developed the new practical method for constructing a 6-carbomethoxymethyl-3-methoxy-1,2-dioxane skeleton in combination with Sc(OTf)_3-mediated peroxyhemiacetalization of keto-esters and intramolecular hetero-Michael addition of peroxyhemiacetals. By application of this procedure, several analogs with linear side chains on C-3 were synthesized and their antimalarial activity was evaluated. Among the synthesized analogs, pentyl analog 8 showed not only potent inhibitory activity for proliferation of Plasmodium falciparum but also higher selective index than 1 and 2. Despite of expecting antimalarial potency in vitro, 8 displayed little potency in a mouse model. This distinct difference in biological scores disclosed that 8 was metabolized to less active carboxylic acid in mouse serum. Substitution of amide function stable in serum for the ester function in 8 led to new antimalarial lead compounds (13, 14) possessing in vivo antimalarial potency. On the other hand, bioassay guided separation of the extracts of crude drugs resulted in isolation of the flavonol glycosides (17-19) from Hydrangeae Dulcis Folium (Amacha in Japanese) as active constituents. As a result of detailed examination of effect on the life cycle of P. falciparum of the flavonol glycosides, the monoglycosides (17, 18) completely inhibited proliferation of P. falciparum, while the diglycoside (19) retarded life cycle of parasite. For the purpose of elucidating target protein of the above antimalarial natural products, biotinylated probes with moderate potency were synthesized.

• 天然有機化合物討論会の論文
• 2002-09-01

著者

• 河西 基之

  阪大院・薬

• 田村 理

  阪大院薬

• 堀井 俊宏

  阪大微研・分子原虫学

• 堀井 俊宏

  阪大微研

• 村上 啓寿

  阪大院薬

• MURAKAMI Nobutoshi

  Kyoto Pharmaceutical University

• 村上 啓寿

  阪大院薬:presto

• Matsumura N

  Res. Foundation Itsuu Lab. Tokyo Jpn

• 小林 資正

  阪大院薬

• 河西 基之

  阪大院薬

• Mostaqul Huq

  阪大院薬

• 板垣 佐和子

  阪大微研

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