13 マレーシア産Mitragyna speciosaに含有される鎮痛性インドールアルカロイドの化学的・薬理学的研究(口頭発表の部)

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Mitragyna speciosa Korth. (Rubiaceae) is a tropical plant indigenous to Thailand and the Malay Peninsula. The leaves of this plant were traditionally used as a stimulant like coca or as a substitute for opium. But the use of this plant is now illegal in these countries because of its narcotism. With the object to clarify pharmacological profiles of this plant species as well as to find new lead-compounds from this medicinal resources, the following studies focusing on the constituents in the leaves of M. speciosa native to Malaysia were carried out. I: Isolation and Structure Elucidation of New Indole Alkaloids from the Leaves of M. speciosa in Malaysia. From the methanol extract of the mature leaves of M. speciosa in Malaysia, six 9-methoxy-Corynanthe-type indole alkaloids, i.e., mitragynine, speciogynine, speciociliatine, paynantheine, mitragynaline, and 7α-hydroxy-7H-mitragynine were isolated. In addition, three new indole alkaloids, 3,4,5,6-tetradehydromitragynine, mitralactonal, and mitrasulgynine carrying a sulfonate function, were isolated and their structures were elucidated by spectroscopic analysis and/or chemical transformation. From the young leaves of this plant, two new alkaloids, named mitralactonine and 9-methoxymitralactonine, were isolated together with six known indole alkaloids. The unique structure of mitralactonine was finally established by total synthesis. Determination of the absolute configuration at the C20 position by means of chiral total synthesis will be presented. II: Studies on the Asymmetric Total Synthesis of a Minor Mitragyna Alkaloid, Speciogynine. First asymmetric total synthesis of speciogynine, which is a minor constituents in M. speciosa and a diastereoisomer of the major component, mitragynine, at the C20 position, was studied. Our basic approach to speciogynine features the utilization of asymmetric desymmetrization of the prochiral cyclic imide to construct the fundamental core structure of Corynanthe-type alkaloids in chiral form. Based on this strategy, the key intermediate, 21-oxo-20-deethyl-speciogynine, having the absolute configuration of the natural alkaloid could be synthesized. The final stages of the total synthesis is currently being investigated. III: Synthesis of the Mitragynine Derivatives, Structure-Activity Relationship, and the Action Mechanisms of the Antinociceptive Activity of the Mitragyna Alkaloids. A potent opioid agonistic property of mitragynine, a major constituent of this plant, and mitragynine pseudoindoxyl, a oxidative derivative of mitragynine, was clarified in vitro experiments. Mitragynine pseudoindoxyl, whose agonistic potency is 20-40 fold greater than that of morphine, acts on mu- and delta-opioid subtype receptors. The essential structural feature for revealing the activity was elucidated by study of the structure-activity relationship using natural and synthetic derivatives.
天然有機化合物討論会の論文
1998-08-31

13 マレーシア産Mitragyna speciosaに含有される鎮痛性インドールアルカロイドの化学的・薬理学的研究(口頭発表の部)

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