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YAKUGAKU ZASSHI, 121(7),467-479, 2001
This article describes a design and synthesis of new and versatile chiral building blocks and its application to the biologically active natural product synthesis. The chiral building blocks were prepared using a biocatalysis in an enantiomerically pure state. As an application of the above chiral building blocks to the synthesis of biologically active natural product, we demonstrated the diastereodivergent synthesis of the 3-piperidinol alkaloids cassine, spectaline, prosafrinine, iso-6-cassine, prosophylline, prosopinine, and also established the flexible route to the 5,8-disubstituted indolizidine or 1,4-disubstituted quinolizidine type of Dendrobates alkaloids. As another application to the synthesis of biologically active alkaloids, we accomplished the first enantioselective total synthesis of marine alkaloids clavepictines A, B, and pictamine using a highly stereoselective Michael type quinolizidine ring closure reaction as the crucial step, and thefirst total synthesis of a marine alkaloid lepadin B was also achieved using aldol cyclization controlled by a A (1,3) strain.
Key words--chiral building blocks; Dendrobates alkaloids; clavepictines; pictamine; lepadin B, A(1,3) strain
YAKUGAKU ZASSHI, 121(7),481-485, 2001
Aeromonas sobria has been recognized as pathogens associated with acute gastroenteritis in both adults and children. The major virulence factor has been proposed to be hemolysin which possesses both hemolytic and enterotoxic activities. Mature (bio-active) hemolysin secreted out of cells binds to the target cells of the host and injure the cells. However, hemolysin remained in bacteria can not express such toxicity. It means that the maturation and secretion pathway of hemolysin is closely related to the pathogenicity of bacteria. Therefore, I examined the pathway and clarified the following events. Hemolysin synthesized in cytoplasm translocates across the inner membrane and appears in a periplasmic space. Hemolysins appeared in the space associates to form dimer in the space. The C-terminal region of hemolysin functions as a trigger in the association. Dimerized hemolysin crosses the outer membrane and emerges in milieu, but monomer can not cross it. Therefore, the C-terminal region of hemolysin attributes not only to the formation of the dimer but also to its secretion into milieu. Hemolysin emerged in milieu is inactive. Inactive hemolysin is converted to bio-Active hemolysin by deleting its carboxyl-terminal 42-amino-acid peptide. Active hemolysin generated binds to the receptor of the target cell and stimulates the production of cyclic AMP by the cell. I assume that this stimulation closely relates to the induction of diarrhea by hemolysin.
Key words--Aeromonas sobria; hemolysin; dimer; diarrhea
YAKUGAKU ZASSHI, 121(7),487-495, 2001
We are developing the synthesis of biologically interesting condensed-heteroaromatic compounds, including natural products by the thermal electrocyclic reaction of 6π electron system incorporating the double bond of the principal aromatic or heteroaromatic ring. In this report, we describe three types of electrocyclic reactions as follows; 1) the synthesis of highly-substituted carbazole alkaloids based on the allene-mediated electrocyclic reaction involving an indole 2,3-bond, 2) the synthesis of β-carboline alkaloids and isoquinoline-5,8-quinone alkaloids based on the thermal electrocyclic reaction of an 1-azahexatriene system involving an indole 2,3-bond or benzene 1,2-bond, and 3) the synthesis of new tetracyclic pyrido[2,3-b]indole, grossularines, based on the thermal electrocyclic of an 2-azahexatriene system including the indole 2,3-bond.
Key words--electrocyclic reaction; azahexatriene; carbazole alkaloids; β-carboline alkaloids; isoquinoline-5,8-quinone alkaloids; α-carboline alkaloids
YAKUGAKU ZASSHI, 121(7),497-521, 2001
The chemical constituents of Cimicifuga simplex and its retated species were reexamined using HPLC and high resolution spectral analysis. From C. simplex, C. acerina and C. japonica, a new alkaloid, 59 new cycloartane triterpene glycosides and 11 new aromatic constituents were isolated with the previously reported compounds. The latter aromatic constituents were identified in HPLC analysis of the extracts from crude drugs due to C. dahurica, C. heracleifolia and C. foetida. Several interesting topics in this study are reviewed about separation of unstable and closely related compounds by HPLC, rearrangement reactions, chemical conversion for confirmation of absolute configuration, isomerism in NMR solutions, X-ray crystal analysis, spectral analysis of complicated structures, isolation of glycoside malonates, high yield of enzymatic hydrolysis, specific CD curve due to a cycloart-7-ene system, and so on. Biological activities of a major glycoside, cimicifugoside, a modified triterpene, acerinol, and benzyltartaric acid derivatives such as fukinolic acid and cimicifugic acids were also mentioned.
Key words--Cimicifuga species; chemical constituent; structural elucidation; biological activity
YAKUGAKU ZASSHI, 121(7),523-534, 2001
The concept of Molecular Science of the Living Organism was described, where the living state is explained as the purposive flows of the quantum mechanically controlled chemical reaction systems which support the homeostasis of the living organism. In the 21st century, the post genomic sequence era, the concept may be a self-evident truth. Molecular Science of the Living Organism was presented in the case of G-proteins: i.e., the atomically controlled mechanism of 1. the carcinogenesis which originates from the point mutation of ras p21, 2. the activation of a receptor protein at the cell membrane, especially in the case of bacteriorhodopsin, 3. the activation of an inactive G-protein by the activated receptor protein.
Key words--Molecular Science of the Living Organism; point mutation of ras p21; carcinogenesis; activation of receptor protein; activation of G-protein; atomically controlled mechanism
YAKUGAKU ZASSHI, 121(7),535-556, 2001
Many isoprenylated flavonoids have been isolated from mulberry trees and related plants (Moraceae). Among them, kuwanons G (13) and H (14) were the first isolated active substances exhibiting a hypotensive effect from the Japanese Morus root bark. These compounds are considered to be formed through an enzymatic Diels-Alder reaction of a chalcone (15) and dehydro-kuwanon C (16) or its equivalent. Since that time, about forty kinds of Diels-Alder type adducts structurally similar to that of 13 have been isolated from the moraceous plants. Some strains of Morus alba as well as M. bombycis callus tissues have a high productivity of mulberry Diels-Alder type adducts, such as chalcomoracin (26) and kuwanon J (28). The biosynthesis of the mulberry Diels-Alder type adducts has been studied with the aid of the cell strain. Chalcomoracin (26) and kuwanon J (28) were proved to be enzymatic Diels-Alder type reaction products by the administration experiment with O-methylchalcone derivatives. Furthermore, for the isoprenoid biosynthesis of prenylflavonoids in Morus alba callus tissues, a novel way through the junction of glycolysis and pentose-phosphate cycle was proposed. The crude enzyme fraction catalyzing the Morus Diels-Alder type reation could be isolated. Studies of phenolic constituents of licorice (Glycyrrhiza species) were carried out. On the course of the structure determination of the phenolic constituents of licorice, two new NMR structure determination methods for prenylflavonoids were found. Furthermore, the prenylphenols isolated from licorice were summarized according to the origin of the materials.
Key words--prenylflavonoid; biosynthesis; mulberry tree; Diels-Alder type adduct; licorice
YAKUGAKU ZASSHI, 121(7),557-565, 2001
This paper described the studies on the mechanism of subcellular distribution of lipophilic weak bases. Although the tissue distribution of basic drugs appeared to decrease with time simply in parallel with their plasma concentration, their subcellular distribution in various tissues exhibited a variety of patterns. Basic drugs were distributed widely in various tissues, but were concentrated in lung granule fraction, where their accumulation was dependent on their lipophilicity and lysosomal uptake. As the plasma concentration of drugs decreased after maximum level, the contribution of lysosomes to their subcellular distribution increased. The uptake of the basic drugs into lysosomes depended both on their intralysosomal pH and on the drug lipophilicity. As the lipophilicity of the basic drugs increased, they accumulated more than the values predicted from the pH-partition theory and raised the intralysosomal pH more potently, probably owing to their binding with lysosomal membranes with or without additional intralysosomal aggregation. These phenomena should be considered as a basis of drug interaction in clinical treatments.
Key words--basic drug; distribution; lysosome; lipophilicity; disposition kinetics