北島 満里子

From the stems of Willughbeia firma Bl., collected in southern Thailand, a fatty acid ester of a triterpenoid, 3-docosanoyl lupeol (1), was isolated as a major component along with lupeol and acetyl lupeol. The structure of 1 was determined by spectroscopic analysis and by synthesizing 1 from natural lupeol and docosanoyl chloride.

On the occasion of the second scientific investigation on ancient medicines stored in Shosoin repository, a chemical study of the constituents of a medicine with the code name N-127, Uyaku-no-zoku ((sic) 127 (sic) ), was carried out. We isolated four indole allialoids, gelsevirine, koumine, gelsemine, and sempervirine, in pure states from the toxic medicine of the 8th century. This result indicates that the medicine is obviously Yakatsu ((sic)) listed in the dedicatory document, Shuju-yaku-cho ((sic)), and the original plant is Gelseriziunz elegans Benth. endemic to southern part of China.

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.

9-beta-D-Glucosyloxycamptothecin, which has been obtained from the regenerated plantlets of Ophiorrhiza pumila, has been synthesized and its structure and the absolute configuration established.

The leaves of Mitragyna speciosa Korth. have been known as an opium substitute in traditional use by Thai and Malay natives. With the object to clarify pharmacological profiles of this plant species as well as to utilize this plant resource as a medicinal development, the following chemical and pharmacological studies were carried out. I: Alkaloids in the leaves of Mitragyna speciosa growing in Thailand. Reinvestigation of the alkaloidal constituents in the leaves of the plant resulted in the isolation of a major indole alkaloid, mitragynine (1), and three minor alkaloids. Furthermore, a new alkaloid (5) was obtained. The structure of 5 was initially deduced by spectroscopic analysis and finally determined to be 7α-hydroxy-7H-mitragynine by chemical transformation from 1. II: Chiral synthesis of mitragynine and its pseudoindoxyl derivative. Starting from an optically pure alcohol (8), an enantioselective total synthesis of mitragynine (1), a major alkaloidal component of this plant, was attained for the first time. Furthermore, 1 was converted into the pseudoindoxyl derivative (18), which had stronger analgesic activity than that of 1. The stereochemistry of the C2, C3 positions in pseudoindoxyls was also investigated. III. Synthetic studies of new Mitragyna alkaloids. To establish the synthetic route of the new skeletal type of indole alkaloids (25, 26) isolated from Malaysian Mitragyna speciosa, we examined the synthesis of a simple alkaloid, nauclefidine (27). As a results, the structure of nauclefidine was revised as formula (31) based on the total synthesis and biomimetic transformation from the vincoside lactam (36). IV: Pharmacological evaluation of the Mitragyna alkaloids. The crude alkaloid mixture and mitragynine showed non-narcotic antinociceptive activities in mice and inhibited contraction of smooth muscle of Guinea-pig ileum. The mechanism of these action will be reported.

For the purpose of contributing to the development of medicinal material, we have continuously studied on the phytochemical investigation of Thai medicinal plants, mainly counting indole alkaloids. In the present study, the alkaloidal constituents of the three Apocynaceae plants, native to the south part of Thailand, were exhaustively investigated. I: Alkaloids from the leaves of Rauwoifia sumatrana Jack. Three new indole alkaloids, rausutrine (1), rausutranine (2), and 11-methoxystrictamine (5), were found from the ethanol extracts of the leaves of this plant, along with ten known bases. Rausutrine and rausutranine are novel bis-indole alkaloids composed of an akuammilane unit and a vincorane unit, the latter of which has a unique iminoquinone function. II: Alkaloids from Hunteria zeylanica (Retz.) Gardn. ex Thw. II-1. Glycosidic alkaloids Two novel glycosidic indole alkaloids, hunterioside (8) and hunterioside B (9), together with strictosidinic acid (6), were isolated from the n-BuOH fraction of the ethanol extracts of the stem bark of this plant, and their structures were respectively found to be 6'-α-glucoside and 3'-α-glucoside of strictosidinic acid. This isolation is the first finding of a biosidic congener of monoterpenoid indole alkaloid glucosides. II-2. A new class of dimeric indole alkaloids and the corymine-related alkaloids Two novel dimeric indole alkaloids, coryzeylamine (14) and deformylcoryzeylamine (15), which are composed of sarpagine-type and echitamine-type monoterpenoid indole alkaloids, were isolated from the leaves of Hunteria zeylanica. Furthermore, the major alkaloidal constituent, corymine (10), and three minor corymine derivatives (11-13), were obtained. III: Alkaloids from Alstonia glaucescens Mona. The first phytochemical investigation of this plant has resulted in the isolation of three new indole alkaloids (17-19) along with five known bases.