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Biomedical subjects

K Toshima

Publications and source records attributed to K Toshima.

At least 19 recordsLinked to original sources
PubMed2001

The first total synthesis of concanamycin f (concanolide a).

A highly stereoselective total synthesis of the macrolide antibiotic concanamycin F (1), a specific and potent inhibitor of vacuolar H(+)-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 18-membered tetraenic lactone and beta-hydroxyl hemiacetal side chain subunits. The C1-C19 18-membered lactone aldehyde 4 was synthesized through the intermolecular Stille coupling of the C5-C13 vinyl iodide 24 and the C14-C19 vinyl stannane 25, followed by construction of the C1-C4 diene and macrolactonization. Synthesis of 4 via a second convergent route including the esterification of the C1-C13 vinyl iodide 45 and the C14-C19 vinyl stannane 47 followed by the intramolecular Stille coupling was also realized. The highly stereoselective aldol coupling of 4 and the C20-C28 ethyl ketone 5 followed by desilylation provided 1 which was identical with natural concanamycin F.

Anti-Bacterial Agents↗
PubMed2001

Involvement of catalytic amino acid residues in enzyme-catalyzed polymerization for the synthesis of polyesters.

Recently, a variety of aliphatic polyesters have been synthesized using hydrolases such as lipases and PHB depolymerases, and the reaction mechanism for these enzyme-catalyzed polymerization has been discussed. In this paper, we have studied the involvement of the catalytic amino acid residues of the hydrolase in enzyme-catalyzed polymerization with an extracellular PHB depolymerase from Alcaligenes faecalis T1. A wild-type PHB depolymerase and three kinds of site-specific mutants (catalytic amino acids were substituted) were prepared and their polymerization activities for the ring-opening polymerization of (R)-beta-butyrolactone (BL) were compared. BL was polymerized at 80 degrees C in bulk by the wild-type enzyme to yield polymers consisting of cyclic and linear structures in a high monomer conversion. In contrast, none of the mutant enzymes showed obvious polymerization activity. These results have clearly demonstrated that the catalytic triad is indeed responsible for the enzyme-catalyzed polymerization of BL.

4-Butyrolactone↗
PubMed2000

Glycosyl fluorides in glycosidations.

This short review deals with the recent progress in chemical O-glycosidation and C-glycosylation methods using glycosyl fluorides as glycosyl donors. Pyranosyl and furanosyl fluorides were effectively activated by fluorophilic reagents such as SnCl2-AgClO4, SnCl2-TrClO4, SnCl2-AgOTf, TMSOTf, SiF4, BF3 x Et2O, TiF4, SnF4, Cp2MCl2-AgClO4 (M = Zr or Hf), Cp2ZrCl2-AgBF4, Cp2HfCl2-AgOTf, Bu2Sn(ClO4)2, Me2GaCl, Tf2O, LiClO4, Yb(OTf)3, La(ClO4)3 x nH2O, La(ClO4)3 x nH2O-Sn(OTf)2, Yb-Amberlyst 15, SO4/ZrO2, Nafion-H, montmorillonite K-10, and TrB(C6F5)4 to react with alcohols to give the corresponding O-glycosides in high yields. Furthermore, several types of C-glycosyl compounds, such as aryl, allyl and alkyl C-glycosyl derivatives, were also obtained by the glycosylation using glycosyl fluorides and the corresponding nucleophile with or without a Lewis acid.

Fluorides↗
PubMed2000

Lipase-catalyzed transformation of poly(epsilon-caprolactone) into cyclic dicaprolactone.

The enzymatic degradation and polymerization using an enzyme were carried out with respect to the establishment of a sustainable chemical recycling system for poly(epsilon-caprolactone) (PCL) which is a typical biodegradable synthetic plastic. The enzymatic transformation of PCL having an Mn of 110,000 using Candida antarctica lipase (lipase CA) in water-containing toluene at 40 degrees C afforded the corresponding cyclic dicaprolactone (DCL, 1,8-dioxacyclotetradecane-2,9-dione) in a yield of up to 97%. Thus the obtained DCL readily polymerized again using both the fresh and recovered lipase CAs.

Candida↗
PubMed1999

2-Phenylquinoline-Carbohydrate Hybrids: Molecular Design, Chemical Synthesis, and Evaluation of a New Family of Light-Activatable DNA-Cleaving Agents.

Artificial intercalator-carbohydrate hybrids such as that shown in the scheme cleave DNA at the site of guanine on irradiation with UV light with a long wavelength. The hybrids also exhibit strong cytotoxicity when irradiated. The hybrid system is very important for DNA cleavage, and the cytotoxic activity correlates with the DNA-cleaving capacity

Journal Article↗
PubMed1999

Expression of osteopontin in Kupffer cells and hepatic macrophages and Stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas.

Activated Kupffer cells and macrophages accumulate in necrotic areas in the liver. Osteopontin, an extracellular matrix with RGD sequence, has been shown to act as a chemokine that can induce monocyte migration. The possibility that osteopontin can play a role in infiltration of both cells into hepatic necrotic areas was investigated in rats. Northern blot analysis revealed that osteopontin mRNA expression was minimal in Kupffer cells and hepatocytes immediately after isolation from normal rats, but slight in hepatic stellate cells assumed nearly quiescent in function after 3 days of culture on plastic dishes. When rat received carbon tetrachloride, liver necrosis developed between 1 and 3 days following the intoxication. In these rats, osteopontin mRNA expression assessed by quantitative competitive RT-PCR was increased in the liver later than 1 day with its peak at 2 days following the intoxication. Kupffer cells and hepatic macrophages and hepatic stellate cells isolated from such liver showed marked expression of osteopontin mRNA on Northern blotting. Immunohistochemical examination disclosed that osteopontin was stained in macrophages including Kupffer cells and stellate cells in the necrotic areas. On electron microscopy, osteopontin stains were present in the Golgi apparatus in these cells. Recombinant human osteopontin promoted migration of Kupffer cells isolated from normal rats and cultured in a Transwell cell culture chamber in a dose-related manner. We conclude that activated Kupffer cells and hepatic macrophages and stellate cells express osteopontin. These cells might contribute to the infiltration of Kupffer cells and macrophages into hepatic necrotic areas by expressing osteopontin.

Animals↗
PubMed1998

Contribution of CD14 to endotoxin-induced liver injury may depend on types of macrophage activation in rats.

Activated Kupffer cells and hepatic macrophages can produce massive liver necrosis through microcirculatory disturbance due to sinusoidal fibrin deposition. This mechanism is involved in the development of liver injury after endotoxin administration in rats pretreated with heat-killed Propionibacterium acnes (P.acnes) or undergoing 70% liver resection. The significance of CD14, a receptor for lipopolysaccharide and its binding protein, was evaluated in both models in relation to the activation mechanisms of Kupffer cells and hepatic macrophages. Northern blot analysis revealed that CD14 mRNA expression was increased in the liver of rats following P.acnes administration. In these rats, hepatic macrophages immediately after isolation showed marked increased of CD14 mRNA expression compared to Kupffer cells from normal rats. In contrast, CD14 mRNA expression was minimal in partially resected liver. Interleukin (IL)-18 and IL-2 mRNA expression in the liver and interferon (IFN)-gamma mRNA expression in the spleen were significantly increased in P.acnes-treated rats compared to normal rats, while these increases were absent in partially hepatectomized rats. Thus, CD14 expressed on hepatic macrophages after activation through a cytokine network of IL-18, IFN-gamma, and IL-2 may contribute to endotoxin-induced liver injury in P.acnes-treated rats. In contrast, in partially hepatectomized rats, this network may not operate during Kupffer cell activation, and the liver injury might develop through endotoxin receptors other than CD14 on the cells.

Animals↗
PubMed1998

The mechanisms of hepatic sinusoidal endothelial cell regeneration: a possible communication system associated with vascular endothelial growth factor in liver cells.

Vascular endothelial growth factor (VEGF) has been shown to induce proliferation of sinusoidal endothelial cells in primary culture. To elucidate the mechanisms of sinusoidal endothelial cell regeneration in vivo, mRNA expression of VEGF and its receptors, flt-1 and KDR/flk-1, were studied in rat livers. Northern blot analysis revealed that VEGF-mRNA was expressed in hepatocytes immediately after isolation from normal rats. In contrast, non-parenchymal cells, including sinusoidal endothelial cells, expressed VEGF receptor-mRNA. Vascular endothelial growth factor-mRNA expression in hepatocytes was decreased during primary culture, but increased following a peak of DNA synthesis, induced by addition of epidermal growth factor or hepatocyte growth factor to the culture medium at 24 h of plating. In a 70% resected rat liver, VEGF-mRNA expression increased with a peak at 72 h after the operation, and mRNA expression of VEGF receptors between 72 and 168 h. In such a liver, mitosis was maximal in hepatocytes at 36 h and in sinusoidal endothelial cells at 96 h. Also, mRNA expression of both VEGF and its receptors was significantly increased in carbon tetrachloride-intoxicated rat liver compared with normal rat liver. Vascular endothelial growth factor expression was minimal in Kupffer cells isolated from normal rats, but marked in activated Kupffer cells and hepatic macrophages from the intoxicated rats. Vascular endothelial growth factor-mRNA expression was also increased in activated stellate cells from these rats and in the cells activated during primary culture compared with quiescent cells. We conclude that increased levels of VEGF expression in regenerating hepatocytes may contribute to the proliferation of sinusoidal endothelial cells in partially resected rat liver, probably through VEGF receptors up-regulated on the cells. Also, VEGF derived from activated Kupffer cells, hepatic macrophages and stellate cells may be involved in this proliferation in injured rat liver.

Animals↗
PubMed1998

Effect of FK506 on the activation state of hepatic macrophages in Propionibacterium acnes-treated rats.

Activated hepatic macrophages can provoke massive liver necrosis following endotoxin stimulation through microcirculatory disturbances due to sinusoidal fibrin deposition in rats pretreated with heat-killed Propionibacterium acnes. In these rats, FK506 (tachlorinus) administered 24 h before and at the time of endotoxin injection, significantly attenuated liver injury compared with the rats given no FK506. The effect of FK506 on hepatic macrophage activation and its action sites were studied in Propionibacterium acnes-treated rats. When rats received Propionibacterium acnes intravenously, hepatic-mRNA expression of interferon-gamma-inducing factor and interleukin-2 and splenic-mRNA expression of interferon-gamma were significantly increased compared with normal rats. Hepatic-mRNA expression of CD14, a receptor for lipopolysaccharide and its binding protein complex, was also increased preceding the expressions of the three cytokines in the liver and spleen. FK506 administration attenuated hepatic-mRNA expression of interleukin-2 and both superoxide anions as well as tumour necrosis factor-alpha production by hepatic macrophages, but did not change CD14-mRNA expression in Propionibacterium acnes-treated rats. It is suggested that a cytokine network through interferon-gamma-inducing factor, interferon-gamma and interleukin-2 may operate during activation of hepatic macrophages in rats treated with heat-killed Propionibacterium acnes, while CD14 expression on the cells may increase independently of this network. FK506 seems to attenuate such activation by suppressing hepatic interleukin-2 expression, without affecting CD14 expression on the cells.

Animals↗
PubMed1996

Novel designed enediynes: molecular design, chemical synthesis, mode of cycloaromatization and guanine-specific DNA cleavage.

The molecular design and chemical synthesis of novel enediyne molecules related to the neocarzinostatin chromophore (1), and their chemical and DNA cleaving properties are described. The 10-membered enediyne triols 16-18 were effectively synthesized from xylitol (10) in a short step, and found to be quite stable when handled at room temperature. The representative and acylated enediyne 16 was cycloaromatized by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in cyclohexa-1,4-diene-benzene to give the benzenoid product 21 through a radical pathway. On the other hand, the enediyne 16 was cycloaromatized by diethylamine in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer to afford another benzenoid product 22 as a diethylamine adduct through a polar pathway. Furthermore, the enediynes 16-18 were found to exhibit guanine-specific DNA cleavage under weakly basic conditions with no additive.

Alkynes↗
PubMed1996

Treatment of hypervascular small hepatocellular carcinoma with ultrasound-guided percutaneous acetic acid injection: comparison with segmental transcatheter arterial embolization.

OBJECTIVE: To compare the efficacy of ultrasound-guided percutaneous acetic acid injection and segmental transcatheter arterial embolization for hypervascular small hepatocellular carcinoma. METHODS: The prognosis of 40 patients with one to three angiographically hypervascular hepatocellular carcinoma smaller than 3 cm in diameter treated with either percutaneous acetic acid injection (25 patients) or transcatheter arterial embolization (15 patients) during the past 4.5 yr were analyzed retrospectively. RESULTS: After initial therapy, none of 25 patients treated with percutaneous acetic acid injection developed ascites, whereas 5 of 15 (33%) patients treated with transcatheter arterial embolization developed it (p < 0.01). All tumors became smaller once after each therapy. However, local recurrence (reenlargement of the original tumor) occurred in 1 of 29 (3%) tumors treated with percutaneous acetic acid injection and 11 of 22 (50%) tumors treated with transcatheter arterial embolization (p < 0.005). During the follow-up, 4 of 25 (16%) patients treated with percutaneous acetic acid injection and 10 of 15 (67%) patients treated with transcatheter arterial embolization died. The 1-, 2-, and 3-yr survival rate was 100, 94, and 83%, respectively, in patients treated with percutaneous acetic acid injection and 72, 65, and 39% in patients treated with transcatheter arterial embolization (p < 0.005). The cancer-free survival rate was also significantly better in the former than in the latter group (p < 0.005). CONCLUSIONS: Percutaneous acetic acid injection is superior to segmental transcatheter arterial embolization in the treatment of hypervascular small hepatocellular carcinoma.

Acetic Acid↗
PubMed1995

Concanamycin B inhibits the expression of newly-synthesized MHC class II molecules on the cell surface.

We screened natural chemical compounds which inhibit the expression of newly-synthesized MHC class II molecules on the cell surface. IFN-gamma stimulates Colo 205 adenocarcinoma cells to induce the expression of MHC class I, MHC class II, and ICAM-1 molecules on the cell surface. We show here that concanamycin B inhibits the expression of MHC class II molecules on Colo 205 cells, whereas it does not affect the expression of MHC class I and ICAM-1 molecules. Concanamycin B also abrogates the enhancement of the MHC class II expression by IL-4 on mouse lymphocytes. Furthermore, concanamycin B suppresses the antigen presentation by MHC class II molecules.

Animals↗
PubMed1994

Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG-->ACG) results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.

Alleles↗