Publications (176)236.94 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- [Show abstract] [Hide abstract] ABSTRACT: A new ellagic acid derivative (1) was isolated from the branches of Combretum yunnanensis, and its structure was assigned as 4-(4' '-O-acetyl-alpha-rhamnopyranosyl)ellagic acid by analysis of its spectral data. Total synthesis of 1 was achieved by the glycosylation of 3,3'-di-O-benzylellagic acid (5) with 4-O-acetyl-2,3-di-O-benzyl-l-rhamnose (4) as a key reaction, and the absolute configuration of 1 was determined. Compound 1 showed weak inhibitory activity against the growth of various tumor cells and inhibited HIV-1 protease.
- [Show abstract] [Hide abstract] ABSTRACT: Two novel triterpenoid saponins with insulin-like activity, termed assamicin I and II, were isolated from the roots of Aesculus assamica Griff. and their structures were characterized as 1 and 2, respectively. They inhibited release of free fatty acids from epinephrine-treated rat adipocytes and enhanced glucose uptake into 3T3-L1 adipocytes.
- [Show abstract] [Hide abstract] ABSTRACT: Gallic acid (GA) and chebulagic acid (CA) were isolated from the extract of a herbal medicine, kashi (myrobalans: the fruit of Terminalia chebula) as active principles that blocked the cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. GA and CA inhibited the killing activity of CD8+ CTL clone at IC50 values of 30 microM and 50 microM, respectively. Granule exocytosis in response to anti-CD3 stimulation was also blocked by GA and CA at the equivalent concentrations.
- [Show abstract] [Hide abstract] ABSTRACT: The nonapeptide leucinostatin A (LSA) inhibited syncytium formation without profoundly affecting HN glycoprotein synthesis in Newcastle disease virus (NDV)-infected BHK cells. At similar doses of LSA, cytopathic effect and infectious virus production were suppressed in vesicular stomatitis virus (VSV)-infected BHK cells. Blockade by LSA of cell surface expression of NDV-HN and VSV-G glycoproteins was demonstrated, accompanied by intracellular accumulation of these virus glycoproteins. LSA acts as an inhibitor of mitochondrial F-type H(+)-translocating ATPase, a key enzyme in the generation of ATP, but its action against cell surface expression of virus glycoproteins was independent of the depletion of intracellular ATP. LSA also acts as an ionophore, but its action on intoxication by ricin and diphtheria toxin was different from that of monensin. This novel action of LSA is expected to be useful in investigation of the mechanism of intracellular trafficking of proteins.
- [Show abstract] [Hide abstract] ABSTRACT: The inhibitory effect of KRN5500, a spicamycin derivative, on the growth of hepatic metastasis of the tissue polypeptide antigen (TPA)-producing human colon cancer COL-1 was examined in severe combined immunodeficient (SCID) mice. Prior to this chemotherapeutic study, we confirmed the high correlation coefficient (r = 0.86, P < 0.01) between plasma TPA levels in athymic nude mice bearing COL-1 and tumor volume. In the chemotherapy of experimental hepatic metastasis induced by intrasplenic injection of COL-1 cells, KRN5500 at 12 mg/kg per day was administered i.v. three times at 4-day intervals. From the start of chemotherapy (day 1), plasma TPA levels in the mice were significantly decreased from 8332 U/l to a minimum of 494 U/l on day 16 and were within the range for intact SCID mice (409-634 U/l). The mean tumor weight was 4.87 g in the liver of untreated mice on day 19 and 0.74 g, in the liver of KRN5500-treated mice, a significant difference, representing a tumor growth inhibition rate of 85%. These results suggest the usefulness of TPA as a tumor marker in an experimental xenograft model. The chemotherapeutic efficacy of KRN5500 against experimental hepatic metastasis indicates that it may be a useful drug for the treatment of patients with hepatic metastases of colon cancer.
- [Show abstract] [Hide abstract] ABSTRACT: New derivatives of spicamycin modified at the fatty acid moieties of the molecule were synthesized and their structure-activity relationships were examined. The antitumor activity was greatly influenced by modification of the fatty acid moieties to tetradecadienoyl or dodecadienoyl analogues exhibiting better antitumor activity against COL-1 human colon cancer xenograft than SPM VIII.
- [Show abstract] [Hide abstract] ABSTRACT: Costunolide and dehydrocostus lactone were isolated from an extract of mokko (Saussurea lappa Clarke) as inhibitors of killing activity of cytotoxic T lymphocytes (CTL). Mokko lactone was also isolated as an inactive compound from the extract. The structure-activity relationship indicated that alpha-methylene-gamma-butyrolactone is required for the inhibitory effect. Costunolide markedly inhibited the granule exocytosis and the production of inositol phosphates in response to anti-CD3 monoclonal antibody (mAb) stimulation at a concentration that did not affect the binding of anti-CD3 mAb. Tyrosine phosphorylation induced by crosslinking of CD3 molecules was significantly inhibited by costunolide in a dose-dependent manner. These results suggest that costunolide inhibits the killing activity of CTL through preventing the increase in tyrosine phosphorylation in response to the crosslinking of T-cell receptors.
- [Show abstract] [Hide abstract] ABSTRACT: A series of SPM VIII analogs were synthesized to investigate the effect of the amino acid moiety on the antitumor activity. The L-threonine analog and the glycylglycine analog of SPM VIII showed much higher cytotoxicity to P388 murine leukemia cells (IC50 5.8 nM and 0.11 nM, respectively) than SPM VIII (IC50 25nM). However, replacement of the glycine moiety with other amino acids greatly reduced the antitumor activity against COL-1 human colon cancer xenograft model. This study indicated that the glycine moiety of SPM VIII is crucial for the antitumor effect.
- [Show abstract] [Hide abstract] ABSTRACT: The antitumor activity of spicamycin analogue SPM VIII against human stomach, breast, lung, colon and esophageal cancers was compared to that of mitomycin C (MMC) in the human tumor-nude mice xenograft model. Comparative studies of SPM VIII given i.v. at 6 mg/kg/day daily for 5 days and MMC given i.v. at 6.7 mg/kg on day 1 revealed that the antitumor spectrum of SPM VIII showed a different pattern from that of MMC and that SPM VIII caused tumor mass reductions in more tumors than did MMC in colon cancers (4/12 versus 1/11). In addition to this study, a comparative study of SPM VIII given i.v. at 12 mg/kg/day 8 times at 3- or 4-day intervals and 5'-deoxy-5-fluorouridine (5'-DFUR) given po at 185 mg/kg/day 5 days per week for 4 weeks showed that SPM VIII had the highest effect on SC-9 human stomach cancer and COL-1 human colon cancer among the 3 compounds, resulting in a significant reduction of tumor mass. Although other pharmacological studies are in progress, these results suggest that SPM VIII might be a novel antitumor compound effective for human cancers including cancer of the digestive organs.
- [Show abstract] [Hide abstract] ABSTRACT: Spicamycin, a nucleoside antibiotic containing fatty acids with a variety of chain lengths (C12-C18), showed potent antitumor activity against human gastric cancer SC-9 and human breast cancer MX-1 in a xenograft model. We have made several semi-synthetic spicamycin analogues (SPMs) which differed in the chain length of the fatty acid moiety, and examined their structure-antitumor activity relationship. The cytotoxic activities of SPMs depended on the chain length of the fatty acid moiety, with dodecanoyl, tetradecanoyl, hexadecanoyl and icosanoyl analogues (SPM VIII, SPM X, SPM XII and SPM XVI) exhibiting the most potent cytotoxic activity against P388 murine leukemia cells. SPM VIII showed the most activity against SC-9 in the human tumor xenograft model with the highest therapeutic index among SPMs. The antitumor activity of SPM VIII was superior to that of mitomycin C.
- [Show abstract] [Hide abstract] ABSTRACT: Gilvocarcin V was chemically transformed to alter its biological activities as well as its solubility by mainly focusing on the vinyl side chain. The oxirane and oxime derivatives showed slightly decreased in vivo antitumor activity, while the aminoethylmorpholine derivative turned out to be soluble in some organic solvents.
- [Show abstract] [Hide abstract] ABSTRACT: 4'-O-Acyl derivatives of doxorubicin, daunorubicin, 13-deoxocarminomycin, 13-deoxo-10-hydroxycarminomycin, 13-deoxo-11-deoxycarminomycin were synthesized through the formation and mild acid hydrolysis of 2-oxazoline intermediates. The antitumor activity of these 4'-O-acyl derivatives against P388 leukemia was similar to or more effective than the parent anthracyclines.
- [Show abstract] [Hide abstract] ABSTRACT: Methods for determining concentrations of a new morpholino anthracycline MX2.HCl and its metabolites in biological samples using reversed-phase high-performance liquid chromatography and fluorescence detection are described. The limits of detection were less than 1 ng/ml for all compounds after extraction from 0.5 ml of plasma using C18 Sep-Pak cartridges and consecutive solvent extraction. The recoveries from rat plasma ranged from 72.0 to 89.3%. The peak-height ratio of the fluorescence intensities of these compounds versus internal standard showed a linear correlation for concentrations up to at least 500 ng/ml in the plasma (correlation coefficient r greater than 0.999). The within-day and between-day precisions of this assay were in the range 0.8-8.7% (n = 5) and 2.0-3.5% (n = 5), respectively. The concentrations of these compounds in the blood and urine can be also determined by a slight modification of the extraction procedure.
- [Show abstract] [Hide abstract] ABSTRACT: We previously reported that MX2, a new morpholino anthracycline, showed marked effects on pleiotropic drug-resistant sublines of murine P388 leukemia in vivo as well as in vitro. In this study we examine the in vitro cytotoxicity against pleiotropic drug-resistant sublines of human tumor cell lines. MX2 was effective against multidrug-resistant sublines of four human tumor cell lines; these cells, having a 4.8- to 200-fold cross-resistance to Adriamycin (ADM) showed only a 0.7- to 2.3-fold resistance to MX2 compared with the sensitive cells. To elucidate the mechanism by which MX2 overcomes multidrug resistance, the intracellular pharmacology of MX2 in human myelogenous leukemia K562 and its ADM-resistant subline (K562/ADM) was examined. Both K562 and K562/ADM cells accumulated MX2 more easily than ADM, and the intracellular accumulation of MX2 attained a steady state in both cell lines within 30 min of incubation at 37 degrees C. The amount of MX2 that accumulated in K562/ADM at a steady state was only 1.3 times lower than that in K562. However, ADM was accumulated slowly in both cell lines compared with MX2, and the intercellular concentration reached a steady state in K562/ADM after 90 min of incubation and in K562 after more than 120 min. K562/ADM cells accumulated a 3.3-fold lower concentration of ADM than K562 after 120 min of exposure. The steady-state concentration of ADM in K562/ADM was 8.3 times lower than that of MX2. In addition, greater than 70% of MX2 was retained in both cell lines after 150 min of incubation in the absence of this drug. Verapamil, a calcium antagonist, hardly augmented the cytotoxicity of MX2 against K562/ADM, and no distinct effect of this drug on both the time course and the maximal level of accumulation of MX2 was observed. Interestingly, MX2 effectively inhibited ATP/Mg2(+)-dependent [3H]vincristine binding to K562/ADM membrane preparations, indicating that MX2 could be transported outside the cell by an active efflux pump. The high intracellular accumulation and retention of MX2 in K562/ADM through the rapid influx of the drug into the cells may be one of the reasons why MX2 circumvents pleiotropic drug resistance.
- [Show abstract] [Hide abstract] ABSTRACT: The temperature-dependent and concentration-dependent 1H NMR studies as well as 13C-relaxation experiments on gilvocarcin V tetraacetate strongly suggest intermolecular stacking of the antibiotic solution.
- [Show abstract] [Hide abstract] ABSTRACT: We cloned six different DNA fragments from a curromycin producing strain, Streptomyces hygroscopicus 358AV2, which confer curromycin-resistance on a curromycin non-producing and sensitive strain, S. hygroscopicus Rgll, a protoplast regenerant of the strain 358AV2. We studied the plasmid pSHR2 carrying one of the DNA fragments. By Southern blot analysis, the cloned DNA sequence in pSHR2 was found to be deleted in the Rgll genome. From the Rgll strain, a curromycin producing revertant A-4 was obtained, indicating that the structural genes for the curromycin biosynthesis and resistance are retained in the Rgll genome. Based on the existence of A-4 and the deletion of the DNA region corresponding to the cloned DNA sequence in the Rgll genome, we conclude that the cloned DNA sequence carries a regulatory gene governing curromycin-resistance but not the resistance gene itself. The smallest DNA region in pSHR2 conferring curromycin-resistance was sequenced, and it was found that there were two small open reading frames (ORF) on each strand of the cloned DNA. In-frame fusion of ORFs to the reporter gene lacZ revealed that one ORF designated cre was indeed translated in vivo. The putative gene product deduced from the cre ORF is a basic and hydrophilic protein having a calculated molecular weight of 6 kdaltons.
- [Show abstract] [Hide abstract] ABSTRACT: New anthracycline antibiotics, 1-hydroxy-11-deoxycarminomycin II and 11-deoxycarminomycin II were produced by a blocked mutant MuW1 of Actinomadura roseoviolacea from epsilon-pyrromycinone and aklavinone, respectively. We found that the enzyme catalyzing hydroxylation at the C-11 position was not lost but was down regulated in the strain MuW1.
- [Show abstract] [Hide abstract] ABSTRACT: 3'-Deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), a morpholino anthracycline derived from 13-deoxo-10-hydroxycarminomycin (R20X2) was 16 times less cytotoxic than R20X2 against cultured P388 leukemia cells. The reduced cytotoxicity of MX2 was not explainable by intracellular or intranuclear concentration of the drug or by its DNA-intercalating activity. Binding of MX2 and R20X2 to DNA was measured, after isolating the DNA fraction from an incubation mixture of the drugs with P388 cells or with calf thymus DNA. The amount of R20X2 bound to the DNA was obviously larger than that of MX2, and was dependent on incubation time. These data suggest that the poor binding activity of MX2 to DNA contributes to its reduced cytotoxicity.
The University of TokyoTōkyō, Japan