64(P-47) 海産毒ガンビ***ールの多様な構造改変体の全合成と構造活性相関(ポスター発表の部)

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Marine polycyclic ether class of natural products, brevetoxins and ciguatoxins being representative, has attracted a great deal of attention of chemists and biologists due to the unusually complex and gigantic molecular architecture as well as potent and diverse biological activities. Gambierol is a marine polycyclic ether isolated as a toxic constituent from the cultured cells of the ciguatera causative dinoflagellate Gambierdiscus toxicus. It is known that gambierol exerts potent toxicity against mice (MLD 50 μg/kg, ip) and the symptoms caused in mice resemble those shown by ciguatoxins, implying that gambierol is also relevant to the ciguatera seafood poisoning. Recently, Inoue et al. have disclosed that gambierol inhibits competitively the binding of brevetoxin PbTx-3 to the voltage-sensitive sodium channel in excitable membranes. However, extremely limited availability of this toxin from natural sources has prevented further detailed biological studies. We have accomplished the first total synthesis of gambierol based on our developed Suzuki-Miyaura coupling-based strategy. Herein we report the structure-activity relationships of gambierol aiming at establishment of a rational basis for the development of probe molecules useful for biochemical studies. There exist only a few precedents of structure-activity relationship studies on marine polyether natural products, probably due to the difficulties of providing ample quantities of these natural products as well as altering the structure of highly gigantic and complex molecules by chemical means. We surmised that these difficulties could be overcome by synthesizing a diverse set of analogues from a simple yet advanced intermediate of the total synthesis (diverted total synthesis). We have synthesized up to 18 structural analogues and evaluated their biological activity. MLD value against mice (ip) was used as an index. It has been shown that the presence of the C28-C29 and C32-C33 double bonds and an appropriate length of the side chain are crucial structural elements for exerting potent toxicity. The C30 axial methyl group was found to enhance the toxicity, but it is not an essential functional group. Partial reduction of the conjugated diene system within the side chain resulted in a great decrease in toxicity. On the other hand, analogues possessing isomeric conjugated diene still displayed significant activity. These suggest that the planar nature of the conjugated diene system would be an important structural feature. Interestingly, modification of the C1 or C6 hydroxyl groups has almost no influence on the toxicity. In the case of 1-deoxy and 1-O-methylgambierol, however, mice death occurred in 45-140 min (3-10 times longer than gambierol and other active analogues), suggesting the possibility that Cl hydroxyl group is relevant to the bioavailability of the molecule.
2004-10-01

64(P-47) 海産毒ガンビ***ールの多様な構造改変体の全合成と構造活性相関(ポスター発表の部)

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