Bermejo A, Tormo J R, Cabedo N, Estornell E, Figadère B, Cortes D
Departamento de Farmacología, Farmacognosia y Farmacodinamia, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
J Med Chem. 1998 Dec 17;41(26):5158-66. doi: 10.1021/jm9706574.
The development of novel styryl lactone derivatives as bioactive compounds and the semisynthesis of both 4,5-dialkoxylated eight-membered-ring lactones with a heptolide skeleton (almuheptolide-A (1) type) and 7-alkoxylated delta-lactones with a saturated furanopyrone skeleton (etharvensin (8) type) have been successfully achieved from the chiral unsaturated alpha-pyrone altholactone (7). This new method is a direct and one-step enantiospecific alkoxylation of altholactone (7) in concentrated acid medium, followed by formation of the eight-membered-ring zeta-lactone. The reaction mechanism operating in the synthesis of the heptolide skeleton is postulated to be a direct Michael-type addition. Concerted opening of both the alpha-pyrone and tetrahydrofuran rings and subsequent intramolecular rearrangement with the ring closure lead to almuheptolide-A (1). This compound (1) and its diacetated derivative (1a) showed potent and selective inhibitory activity toward mammalian mitochondrial respiratory chain complex I. This mechanism of action, reported here for the first time, provides a possible explanation for the cytotoxic and antitumor activities previously described for related natural compounds.
已成功从手性不饱和α-吡喃酮阿尔托内酯（7）制得新型苯乙烯基内酯衍生物作为生物活性化合物，并半合成了具有庚内酯骨架的4,5-二烷氧基化八元环内酯（阿尔穆庚内酯-A（1）型）和具有饱和呋喃并吡喃酮骨架的7-烷氧基化δ-内酯（乙鸦胆子素（8）型）。这种新方法是在浓酸介质中对阿尔托内酯（7）进行直接的一步对映体特异性烷氧基化反应，随后形成八元环ζ-内酯。推测在庚内酯骨架合成中起作用的反应机理是直接的迈克尔型加成反应。α-吡喃酮环和四氢呋喃环同时开环，随后进行分子内重排并闭环生成阿尔穆庚内酯-A（1）。该化合物（1）及其二乙酰化衍生物（1a）对哺乳动物线粒体呼吸链复合物I表现出强效且选择性的抑制活性。此处首次报道的这种作用机制，为先前所述相关天然化合物的细胞毒性和抗肿瘤活性提供了一种可能的解释。
