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Volume 64, Issue 5
Displaying 1-11 of 11 articles from this issue
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Kuniaki Tatsuta2006 Volume 64 Issue 5 Pages 458-470
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSHerein are described the first total syntheses of some bioactive compounds, which have been accomplished in my laboratories by a variety of strategies and methodologies to clarify their structure-activity relationships and to create practically useful lead compounds for new medicines. The target molecules are antibiotics (tylosin, oleandomycin and tetracycline), antifungals (nanaomycin D and kalafungin), antitumors (lymphostin and BE-54238 B), glycosidase inhibitors (cyclophellitol and nagstatin), peptidase inhibitors (pyrizinostatin, antipain and chymostatin), nervous systemaffecting products (deacetyl-caloporoside, calbistrin A and ES-242-4), mussel-attachment inhibitors (sideroxylonal B and C), anti-pylori (PC-3 and YM-30059), TPO receptor agonist (xanthocillin X dimethylether), and so on.View full abstractDownload PDF (1622K) -
Masaki Kita, Emi Sakai, Daisuke Uemura2006 Volume 64 Issue 5 Pages 471-480
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSThe discovery of a new chemical substance frequently triggers a breakthrough in basic science. Various natural products with extraordinary structures and significant biological activities have been isolated and characterized from marine organisms. These bioactive compounds are candidates for drugs or biological probes for physiological studies. It is still important to search continually for unexpected and unforeseen compounds from nature. To overcome the difficulty of targeted pursuit for such bioactive key compounds, careful observation in the field is extremely important.
We describe here the isolation, structure, biological activities, and synthetic studies of two novel marine secondary metabolites : symbioimine and haterumalide. Symbioimine, isolated from the cultured dinoflagellate Symbiodinium sp., inhibited the differentiation of RAW 264 cells into osteoclasts. Thus, symbioimine is an antiresorptive drug candidate for the prevention and treatment of osteoporosis. Haterumalides, 14-membered cytotoxic macrolides from the Okinawan sponge Ireinia sp., shows potent cytotoxicity.View full abstractDownload PDF (1745K) -
Aiming at the Understanding of the Polvmorhhous Functions at the Molecular LevelHiromune Ando, Hideharu Ishida, Makoto Kiso2006 Volume 64 Issue 5 Pages 481-491
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSFor the purpose of the scrutiny of multi-functions of oligosaccharides at the molecular level, the practical method for the chemical construction is essential. In 1989, we have established the practical method for α-selective sialylation that utilizes nitrile solvent effect to fashion thermodynamically-disfavored equatorial glycoside. Due to the powerful method, we have succeeded in many first syntheses of sialyl oligosaccharide complexes such as sialyl Lewis X, GQ 1 b.
Recently, we have developed highly reactive N-Troc-protected sialyl donor and 1, 5-lactamized sialyl acceptor. N-Troc sialyl donor enabled us to perform high-yielding sialylation, and obtained sialoside could be pivotally derived into various homologues containing Neu 5 Gc, NeuNH2 and 8-O-sulfo-Neu 5 Ac. Further, the synergic coupling with 1, 5-lactamized acceptor produced α(2-4) -and α(2-8) -linked disialic acid sequences in high yields, thereby resulting in the first synthesis of glycan portions of gangliosides HLG-2 and Hp-s 6.View full abstractDownload PDF (1654K) -
Kiichiro Totani, Shinya Hagihara, Yukishige Ito2006 Volume 64 Issue 5 Pages 492-501
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSHigh-mannose-type oligosaccharides, which are co-translationally introduced to nascent polypeptides, play important roles in protein quality control. This process is very complex, involving a number of lectins, chaperones and glycan processing enzymes. For example, calnexin (CNX) and calreticulin (CRT) are molecular chaperons that recognize mono-glucosylated form of high-mannose-type glycans. UDP-Glucose : glycoprotein glucosyltransferase (UGGT) only glucosylates high-mannose-type glycans of unfolded glycoproteins. Fbs 1 is a part of ubiquitin ligase that recognizes sugar chains. Although recent studies have clarified properties of these proteins, most of them used oligosaccharides derived from natural source, which contain structural heterogeneity. In order to gain a precise insight about protein quality control, we comprehensively synthesized high-mannose-type glycans associated with protein quality control system. Additionally, during our investigations of artificial glycoproteins having homogeneous oligosaccharides, a novel non-peptidic substrate for UGGT was discovered. Using these synthetic oligosaccharide probes, we quantitatively evaluated the activity of CRT, Fbs 1 and UGGT.View full abstractDownload PDF (1972K) -
Nobuaki Matsumori, Tohru Oishi, Michio Murata2006 Volume 64 Issue 5 Pages 502-514
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSAmphotericin B (AmB) is known to assemble together and form an ion channel across biomembranes. The selective toxicity is generally accounted for by its higher affinity for ergosterol than cholesterol. To better understand the ion-channel structure and intermolecular interactions, we prepared various AmB derivatives and measured their activities. AmB dimers which are covalently linked between the amino groups by short chains showed more potent ion-channel activity than that of AmB, indicating that the mutual topology of AmB molecules is a head-to-head orientation. AmB-sterol conjugates were also designed and examined for ion-channel activities. AmB-ergosterol conjugates showed more powerful ion-channel activity than AmB-cholesterol congeners, suggesting that stronger van der Waals interaction between AmB and ergosterol contributes to the higher ion-channel activity. Finally, we prepared conformation-restricted derivatives of AmB, in which the amino and carboxyl groups were bridged with various lengths of alkyl chains. The derivatives successfully gave us information on the active-conformation of the sugar moiety of AmB in membrane. These derivatives are now labeled by 13C and/or 19F to probe the molecular structure of AmB ion channel using solid-state NMR.View full abstractDownload PDF (2408K) -
Go Hirai, Tadashi Shimizu, Mikiko Sodeoka2006 Volume 64 Issue 5 Pages 515-528
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSProtein kinase C (PKC) is a family of enzymes which play important roles in intracellular signal transduction. We designed a series of novel PKC ligands having an isobenzofuranone (IB) template, based on the proposed interaction of DAG (1, 2-diacyl-sn-glycerol) with PKC. Since interaction of the hydrophobic alkyl chain of the IB derivatives with lipid membrane is expected to be critical for the PKC activation, we were interested in the synthesis of the IB derivatives having the hydrophobic alkyl chain at various positions of the benzene ring. Effects of these synthetic ligands on the PKCα phosphorylation activity were examined. Surprisingly, 4-substitued derivative showed no activation of PKCα even at high concentration at which significant binding to PKCα was observed. These results suggest that position of the hydrophobic chain is critical for the PKC activation.View full abstractDownload PDF (2776K) -
Ayato Sato, Motonari Uesugi2006 Volume 64 Issue 5 Pages 529-538
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSIn human history, small organic molecules have been utilized for improving human health and for revealing secrets of life. Discovery or design of small organic molecules with unique biological activity permits small-molecule-initiated exploration of biology and further understanding of human diseases. Our laboratory has been discovering and designing bioactive small synthetic molecules to use them as tools to explore biology. This personal perspective summarizes our contributions to chemical biology, particularly in the fields of gene transcription, library design, and growth factor signaling.View full abstractDownload PDF (1616K) -
Kazuo Nagasawa, Jun Shimokawa2006 Volume 64 Issue 5 Pages 539-547
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSThe stereoselective synthetic method for anti-and syn-fused tricyclic guanidine compounds 14 and 19 were developed by a successive 1, 3-dipolar cycloaddition reaction of nitron with two olefins. These two compounds, 14 and 19, were applied for the relative stereochemistry determination of batzelladine F (5) left hand tricyclic guanidine moiety. Based upon this strategy, asymmetric total syntheses of batzelladine A 1 and batzelladine D (3) were also achieved. With the synthetic 1 and 3 in hand, their target protein was examined using immobilized CD 4 and gp 120 affinity gels. The results indicated that batzelladines A (1) and D (3) bind specifically to CD 4.View full abstractDownload PDF (1467K) -
Michio Ichimura2006 Volume 64 Issue 5 Pages 548-558
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSThe microbial screening is an approach for discovering medicines out of microbial metabolites. The natural products (microbial metabolites) are known to possess very unique and complicated structure that could not be imagined. In addition, many of them also have highly potent and selective (specific) biological activities. This report focuses on the feature and present situation of microbial screening in drug discovery field. Firstly, the recent study and development on antitumor antibiotics, duocarmyicins (related compounds) and calicheamicin γ1IIthat indicate extraordinary potent activity, are reviewed. Next, the biochemical and pharmacological study on KS-505a (C 40 tetraterpenoid) produced by Streptomyces argenteolus, a PDE 1 (calcium/calmodulin-dependent phosphodiesterase) isoform selective inhibitor, is presented. The relationship between the microbial screening and recent “chemical biology” or “chemical genetics” approach is also discussed, using for examples, the mode of action of rapamycin and stem cell-based medicine. Finally, the basic strategy in microbial screening (method, target diseases etc.) is described.View full abstractDownload PDF (1989K) -
Ken-ichi Kurihara, Rie Shinei, Tsuneo Okonogi2006 Volume 64 Issue 5 Pages 559-572
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSIn the course of our microbial screening studies to find novel nonsteroidal PR ligands, the fungal metabolites PF 1092 A, B and C were isolated from extracts of cell cultures of the rare fungus Penicillium oblatum PF 1092. We initially sought to identify the minimal pharmacophore by totally synthetic methods, and then clarified the structure-activity relationships (SAR) of PF 1092 (tetrahydronaphthofuranone) derivatives. SAR studies revealed that substituents at the 6-and 7-positions were critical for PR binding affinity and for agonist or antagonist activity. Furthermore, we synthesized tetrahydrobenzindolones possessing a lactam ring, which are chemically more stable than tetrahydronaphthofuranones and generally showed higher PR binding affinity than the corresponding tetrahydronaphthofuranones. The effects of representative antagonists, 37d and 49f, and representative agonists, 51c and 53a were confirmed in in vivo tests. In this report, we mainly describe the synthesis and SAR of these derivatives, as new nonsteroidal PR ligands.View full abstractDownload PDF (1894K) -
[in Japanese], [in Japanese], [in Japanese], [in Japanese], [in Japane ...2006 Volume 64 Issue 5 Pages 573
Published: May 01, 2006
Released on J-STAGE: October 20, 2010
JOURNAL FREE ACCESSDownload PDF (188K)
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