New glycopeptide antibiotics. I. The structures of orienticins.
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Biomedical subjects
Publications and source records attributed to Y Terui.
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Relationships between intrinsic antibacterial activity and beta-lactam chemical reactivity of 7 beta-(phenylacetamido)-7 alpha-methoxy-1-oxacephems with various 3'-substituents were studied in order to clarify the effect of the 3'-substituent on the antibacterial activity. The chemical reactivity of the beta-lactam ring estimated by pseudo-first-order rate constants log kobsdNMR of alkaline hydrolysis at pD 10.4 and 35.0 degrees C correlates well linearly with 13C NMR chemical shift differences (delta delta(4-3], infrared stretching frequencies of the beta-lactam carbonyl (vC = O), and sigma I values. Values of log (1/CN), averaged for the MIC values for Escherichia coli, E. coli NIH JC-2, E. coli EC-14, and Klebsiella pneumoniae SRC-1, were taken as an estimation of the intrinsic antibacterial activity. The log (1/CN) values of the compounds without good leaving groups correlated fairly well with log kobsdNMR values. The comparatively high antibacterial activity of compounds with good leaving groups may be attributable to the different course of decomposition of these compounds.
The degradation process of oxacephems with various 3'-substituents in alkaline solution was examined by 1H NMR spectroscopy, and the structures of two types of degradation products were determined: the hydrolysis products having the cleaved beta-lactam ring and the remaining 3'-substituents, and the exo-methylene compounds having the cleaved beta-lactam ring and the expelled 3'-substituents. The oxacephems were found to decompose, giving the former compounds that subsequently decomposed to the latter compound. Although the ratios of the formation of the exo-methylene compound 15 relative to the other degradation products depended on the leavability of the 3'-substituents, there was little correlation between the relative yields and the beta-lactam reactivity. Thus, the expulsion of the leaving group at the 3'-position was concluded to be not involved in the nucleophilic attack on the beta-lactam carbonyl.
The chemical structures of three new monobactams, PB-5266 A, B and C, were elucidated by their physico-chemical properties and spectrometric studies. In contrast to previously described monobactams, they all possess a dehydroasparagine residue.
When human myeloid and monocytoid leukemic cell lines HL-60 and U937, respectively, were treated with an exogenous sialoglycosphingolipid, ganglioside GM3, in serum-free medium, cell growth was markedly inhibited, and their morphological maturation along a monocytic lineage was observed. In addition to a significant increase in phagocytic and nonspecific esterase activities, marked increase of monocyte-specific surface antigens detectable with monoclonal antibodies such as OKM1 and OKM5 was observed in GM3-fed cells. Other sialoglycosphingolipids with the carbohydrate structure belonging to ganglio-series oligosaccharide, ganglioside GM1 and a brain ganglioside mixture, had no effect on the cell differentiation, showing instead stimulatory actions on the growth of these cell lines. We recently demonstrated that the ganglio-series ganglioside GM3 characteristically increased during macrophage-like cell differentiation of these cell lines. The present results indicate that ganglioside molecular species that specifically increase during monocytic cell differentiation of human myeloid and monocytoid leukemic cell lines may play, in turn, an important role in the differentiation-induction of these cell lines along a monocytic cell lineage.
A remarkable increase in monosialo-ganglioside GM3 was observed during the monocytic differentiation of HL-60 cells induced by 12-0-tetradecanoyl-phorbol-13-acetate(TPA). On the other hand, when the cells were cultured with exogenously-added ganglioside GM3 in serum-free conditions, their differentiation along a monocytic lineage was demonstrated with simultaneous complete growth inhibition. Other gangliosides such as ganglioside GM1 showed no effects on cell differentiation, exhibiting instead stimulatory actions on the cell growth. These results indicate that a physiologically-existent, membranous ganglioside GM3, which specifically increases during monocytic cell differentiation, might play a primary role as a trigger in the monocytic cell differentiation.
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