北島 満里子

Three new gelsedine-type oxindole alkaloids, GS-1, GS-2, and GS-3, and one new iridoid, GSIR-1, were isolated from the stems and leaves of cultivated Carolina jasmine (Gelsemium sempervirens AIT. f.) and their structures were determined by spectroscopic analysis.

Mitragynine (1) is a major alkaloidal component in the Thai traditional medicinal herb, Mitragyna speciosa Korth., and has been proven to exhibit analgesic activity mediated by opioid receptors. By utilizing this natural product as a lead compound, synthesis of some derivatives, evaluations of structure-activity relationship, and surveys of intrinsic activities and potencies on opioid receptors were studied, as follows. Initially, a variety of mitragynine derivatives were prepared, which included the modification of the substituent at C9 and of the indole nucleus. During this study, we found unusual dimerization reactions of indole alkaloid at C7, when phenyliodine (III) bis (trifluoroacetate) (PIFA) or Pb(OAc)_4, was used. This finding led us to develop a concise total synthesis of meso- and rac- chimonanthines (25 and 26). An indole alkaloid, mitragynaline, was first isolated from the young leaves of Malaysian Mitragyna speciosa Korth. and its chemical structure was proposed in 1991. In the present study, we concluded the structure of mitragynaline to be formula 28 by exhaustive NMR analysis at low temperature, by partial synthesis from mitragynine (1), and finally by X-ray analysis. Opioid agonistic activities of mitragynine-related compounds were evaluated by their ability to inhibit the electrically-induced twitch contraction with guinea-pig ileum preparation. Their affinities for μ,δ, and κ-receptors were determined in a receptor-binding assay. As the result, the essential structural moieties in the Corynanthe type indole alkaloids for inducing the opioid agonistic activity were clarified. It was found that the methoxy group on the indole ring at the C9 position is essential structural function for opioid agonistic activity. Interestingly, with altering the functional group at the C9 position, i.e., OMe→OH→H, of mitragynine, the activities of compounds dramatically shifted from that of full agonists through partial agonists to that of antagonists on opioid receptors. Mitragynaline (28) was found to exhibit a potent antagonist for opioid receptors. The oxidative derivatives of mitragynine, i.e., 7-hydroxymitragynine (5) and mitragynine pseudoindoxyl (19), were found as opioid agonists with higher potency than morphine in experiment with guinea pig ileum. In addition, 5 induced a potent analgesic activity in the tail flick test in mice. Especially, this compound showed remarkable antinociceptive activity at oral administration in mice. In conclusion, we could find a promising lead-molecule for the development of new type of analgesics, which were structurally different from morphine.

The antioxidative constituents isolated from Hedyotis diffusa were identified as quercetin 3-O-β-rutinoside (1) and quercetin 3-O-β-glucoside (2). We also isolated asperuloside (3) from this plant. Identification was done based on spectroscopic analysis. Quercetin 3-O-β-rutinoside was the stronger antioxidant than quercetin 3-O-β-glucoside while asperuloside was inactive.

The fragmentation from β-carboline-type monoterpenoid glucoindole alkaloids to harman, which is a hypothetical pathway to generate simple β-carbolines, was actualized in the collision-induced dissociation in MS.

A number of indole and oxindole alkaloids have been isolated from the Uncaria plants (Rubiaceae) and found to possess pharmacologically significant activities. The chemical investigation of Uncaria attenuata Korth in Thailand was first carried out by UK-Thai researchers, resulting in the isolation of many Corynanthe- and heteroyohimbine-type indole and oxindole alkaloids. By the chemical re-investigation of this plant, we found novel types of oxindole alkaloids, i.e., Us-7 (1), Us-8 (2), and Us-9 (3a, 3b). Their structures have been deduced based on spectroscopic analysis and biogenetic speculation. In order to elucidate the structures unambiguously, we carried out the synthesis of these alkaloids. I. Based on the biogenetic speculation, Us-7 (1) and -8 (2), D-seco Corynanthe-type oxindole alkaloids, would be formed from normal corynanthe-type compounds through an oxidative cleavage at the enamine double bond at the C_<20>-C_<21> positions. According to this hypothesis, the stereochemistry at the C15 is most likely to be R. To elucidate the structures including the absolute stereochemistry at C15, we planned the asymmetric total synthesis of Us-7 (1) and -8 (2). Starting from (S)-glycidol (4), a chiral (R)-γ-butenolide (10) was prepared via 7 steps reactions, which was then converted to a key intermediate (14), corresponding to the monoterpenoid part of the target molecules, through a stereoselective addition of a malonate derivative (11) to the butenolide (10). Condensation of 14 with tryptamine (15) gave the lactam (16), which was transformed to the tetrahydro-β-carboline derivatives (20a, 20b) via Bischler-Napieralski reaction and N_b-formylation. The structure of 20a was determined by X-ray crystallographic analysis. The thus obtained indoles were respectively converted to oxindole derivatives. Their stereochemistry at C7 was elucidated by the comparison of CD spectra as well as NOE experiments. The final stage, i.e., hydrolysis of the acetyl ester at C20 and oxidation of the resulting secondary hydroxy group leading to Us-7 (1) and -8 (2), is in progress. II. Us-9 (3a, 3b) was deduced to be 3-oxo-7-hydroxy-3,7-secorhynchophylline by spectroscopic analysis. Based on the biogenetic speculation, Us-9 was prepared from isorhynchophylline via modified Polonovski reaction of its N-oxide and then the introduction of a hydroxy group at the C7. Two diastereomers ascribable to C7 of the natural and semi-synthetic (3a, 3b) were separated by chiral column chromatography. The absolute configulation at C7 was elucidated by comparison of the CD spectra with those of the known oxytryptophan derivatives (28a, 28b), which were prepared from L-tryptophan by Labroo's procedure.

The structure including the stereochemistry of a novel monoterpenoid isoquinoline alkaloid, alangine, was confirmed by total synthesis via N-acyliminium cyclization to construct the isoquinoline skeleton and reductive cleavage of vinyl epoxide with Pd(0) catalyst.

A new prenylated flavone, named artoindonesianin L (1), was isolated from Artocarpus rotunda (Hout) Panzer (Moraceae). Its structure was elucidated as on the basis of spectroscopic evidence. Along with this new compound, four known phenolic compounds were also isolated from this plant and identified as artonins M (2) and E (3), cycloartobiloxanthone (4) and artonin O (5). All these compounds showed significant cytotoxicity against murine P388 leukemia cells. (C) 2001 Elsevier Science B.V. All rights reserved.

A simple β-carboline alkaloid, barman (1), could be isolated from Peruvian Una de Gato which produces β-carboline-type monoterpenoid glucoindole alkaloids along with eight known heteroyohimbine- and corynantheine-type oxindole alkaloids.

Una de Gato (Cat's claw) is a Peruvian traditional herbal medicine for the treatment of various ailments including arthritics, inflammation and cancer. The original plants of Una de Gato are known to be Uncaria tomentosa and U. guianensis (Rubiaceae). By chemical investigation of Peruvian Una de Gato (Original plant: U. tomentosa), a number of indole-related alkaloids and triterpenoids, including new natural products, were isolated as follows. A new glucoindole alkaloid, 3, 4-dehydro-5(S)-5-carboxystrictosidine (1), was obtained from the MeOH extract together with two known glucoindole alkaloids, 5(S)-5-carboxystrictosidine (2), one of the main constituents of this herbal medicine, and a β-carboline-type alkaloid, lyaloside (3). Facile exchange of the methylene hydrogens on C-14 in 1 with deuterium was observed when it was dissolved in CD_3OD. We demonstrated a similar proton-deuterium exchange on a model compound, 1-methyl-3,4-dihydro-β-carboline, in a CD_3OD solution. To establish the structure of 1 including the absolute configuration, 1 was synthesized from secologanin and L-tryptophan through a Bishler-Napieralski reaction. On the basis of our proposal, namely simple β-carboline alkaloids such as harman (9) would be formed from β-carboline-type monoterpenoid alkaloids through fragmentation in some plants, we reinvestigated the non-glucosidic alkaloids in this herbal medicine to confirm the co-existence of harmans. As anticipated, harman (9) itself could be isolated together with eight known Heteroyohimbine-(12-16) and Corynantheine-type (17-19) oxindole alkaloids. The fragmentation from β-carboline-type monoterpenoid glucoindole alkaloids to harmans was actualized in the collision-induced dissociation (CID) measurement in MS. From the MeOH extract of Peruvian Una de Gato, two new 6-keto-triterpenes (20, 21) and 27-nor-ursan-type triterpene (22) were isolated together with nine known triterpenes. The structures of the new compounds were deduced from the spectroscopic data. To confirm the proposed structure of 20, a chemical correlation of 20 with a known triterpene (23) was carried out.

The genus Pandanus belonging to the family Pandanaceae comprises about 600 species, which distribute widely in tropical and subtropical regions. Several Pandanus species are recognized as medicinal plants. Recently, a new skeletal type of alkaloids possessing a γ-alkylidene-α, β-unsaturated γ-lactone or γ-alkylidene-γ, β-unsaturated γ-lactam moiety has been isolated from Pandanus amaryllifolius. Since the Pandanus plants are potentially valuable as candidates for new medicinal resources, we have started chemical studies of Pandanus plants. Isolation and Structure Characterization of Two New Pandanus Alkaloids From the alkaloidal fraction, which was prepared by conventional procedure from an ethanol extract of the fresh leaves of P. amaryllifolius from Thail market, two new alkaloids, pandamarilactonine-A (1) and ?B (2), could be isolated together with a known compound, pandamarilactone-1 (3). By the spectral analysis (UV, IR, MS, 1D and 2D-NMR), the structures of two new compounds have been elucidated except for the stereochemistry of the vicinal asymmetric center at C-14 and C-15 positions. Then, PFG J-HMBC 2D method was applied with a combination of differential NOE experiments to establish the relative stereochemistry at C-14 and C-15 in 1 and 2 (Figure 4). From these data, we propose that pandamarilactonine-A (1) has erythro and pandamarilactonine-B (2) has threo structures. Biomimetic Total Synthesis of Pandamarilactonine-A (1) and -B (2) The biosynthetic route of new Pandanus alkaloids was assumed as shown in Figure 5. We planned a total synthesis of 1 and 2, which mimics the final stage of the biosynthesis proposed above (Figure 6). The key symmetrical amine, which corresponded to the hypothetical biogenetic intermediate, was prepared from benzylamine (10) via 6 steps sequence. Thus obtained crude amine was treated with a catalytic amount of TFA in CH_3CN to give pandamarilactonine-A (1) and -B (2) in 13% and 11% yield, respectively, which were identical with the natural products. Thus, we succeed in the first and biomimetic total synthesis of new alkaloids. Optical Purity of Natural Pandamarilactonine-A (1) and -B (2) Natural (1) exhibited [α]_D^<23>+35.0 (c 4.37, CHCl_3); on the contrary, the specific rotation of natural (2) was almost zero. We were interested in the optical purity of these natural products. With the synthetic racemate in hand, we examined the resolution of the enantiomers using chiral column chromatography. As a result, it was found that natural (1) contained dominantly the (+)-enantiomer in the ratio of 63:37 (Figure 7), while natural (2) existed as a racemate.