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Biomedical subjects

T Sunazuka

Publications and source records attributed to T Sunazuka.

At least 19 recordsLinked to original sources
PubMed2001

An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria.

Infections with parasitic helminths are important causes of morbidity and mortality worldwide. New drugs that are parasite specific and minimally toxic to the host are needed to counter these infections effectively. Here we report the finding of a previously unidentified compound, nafuredin, from Aspergillus niger. Nafuredin inhibits NADH-fumarate reductase (complexes I + II) activity, a unique anaerobic electron transport system in helminth mitochondria, at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep. Thus, our study indicates that mitochondrial complex I is a promising target for chemotherapy, and nafuredin is a potential lead compound as an anthelmintic isolated from microorganisms.

Administration, Oral↗
PubMed2000

Synthetic conversion of ACAT inhibitor to acetylcholinesterase inhibitor.

Natural product acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor pyripyropene A was synthetically converted to acetylcholinesterase (AChE) inhibitor via heterolitic cleavage of the 2-pyrone ring, followed by gamma-acylation/cyclization with several aroyl chlorides. The 4-pyridyl analogue selectively showed AChE inhibitory activity (IC50 7.9 microM) and no ACAT inhibitory activity IC50 = >1000 microM.

Cholinesterase Inhibitors↗
PubMed2000

Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells.

Erythromycin (EM), and related 14-member macrolide antibiotics, has attracted attention for its effectiveness in airway diseases including diffuse panbronchiolitis and sinobronchial syndrome. However, its molecular mechanisms remain unknown. We evaluated the effects of EM on activation of several transcription factors, including nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) in human bronchial epithelial cell line BET-1A, which are known to regulate the expression of many proinflammatory cytokines and chemokines such as interleukin-8 (IL-8). BET-1A cells were cultured with hormonally defined Ham's F12 medium, and were stimulated by phorbol myristate acetate (PMA). EM suppressed mRNA expression as well as the release of IL-8 at therapeutic and noncytotoxic concentrations (% inhibition of IL-8 protein release: 42.2 +/- 5.5%, at 10(-6) M). Furthermore, electrophoretic mobility shift assays revealed that EM inhibited the activations of NF-kappaB and AP-1 induced by PMA in BET-1A cells. These data indicate that EM has inhibitory effects not only on the mRNA expression and release of IL-8, but also on the activation of transcription factors NF-kappaB and AP-1. Our findings support the concept that the recruitment of neutrophils in airway diseases may be regulated by NF-kappaB and AP-1.

Bronchi↗
PubMed2000

Three-dimensional structure-activity relationship analysis between motilin and motilide using conformational analysis and a novel molecular superposing method.

Motilide, an erythromycin derivative, has been shown to equal activity to that of motilin as an agonist at the motilin receptor. However, there is little information on the three-dimensional (3D) structure-activity relationship between these two molecules, largely because they have quite different structures. In this study, we applied a rational computational procedure consisting of conformational analysis and a novel superposing method to investigate the 3D structure-activity relationship between motilide and motilin. We propose common 3D structural features between these molecules, which may be important for their similar activity.

Erythromycin↗
PubMed2000

Reversal of multidrug resistance by 7-O-benzoylpyripyropene A in multidrug-resistant tumor cells.

7-O-Benzoylpyripyropene A (7-O-BzP), a semi-synthetic analog of pyripyropene, was investigated for its reversing effect on multidrug-resistant (MDR) tumor cells. 7-O-BzP (6.25 microg/ml) completely reversed resistance against vincristine and adriamycin in vincristine-resistant KB cells (VJ-300) and adriamycin-resistant P388 cells (P388/ADR), respectively. 7-O-BzP alone had no effect on the growth of drug sensitive and drug-resistant cells. 7-O-BzP (6.25 microg/ml) significantly enhanced accumulation of [3H]vincristine in VJ-300 cells and completely inhibited the binding of [3H]azidopine to the P-glycoprotein in VJ-300 cells and P388/ADR cells. The result suggests that 7-O-BzP effectively reverses P-glycoprotein-related MDR by interacting directly with P-glycoprotein in drug resistant VJ-300 and P388/ADR cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Arisugacins C and D, novel acetylcholinesterase inhibitors and their related novel metabolites produced by Penicilium sp. FO-4259-11.

The mutant of Penicillium sp. FO-4259, an arisugacins A and B producing strain, was found to produce a series of metabolites, designated arisugacins C, D, E, F, G and H, which were structurally related to arisugacins A and B. These compounds were isolated from the culture broth and the physico-chemical and biological properties were examined. The IC50 values of arisugacins C and D against acetylcholinesterase (AChE) were 2.5 microM and 3.5 microM, respectively. However arisugacins E, F, G and H did not inhibit AChE at 100 microM. Though they showed only weak or no activity against AChE compared with arisugacins A and B, they may be useful for the study of the structure-activity relationship.

Cholinesterase Inhibitors↗
PubMed1999

Differential inhibition of HMG-CoA synthase and pancreatic lipase by the specific chiral isomers of beta-lactone DU-6622.

A synthetic beta-lactone trans-DU-6622 (3-hydroxy-2-(hydroxymethyl)-5-[7-(methylcarbonyl)-naphthalen++ +-1-yl]pentanoic acid 1,3-lactone, a mixture of (2R, 3R)- and (2S, 3S)-beta-lactones) was found to inhibit HMG-CoA synthase (IC(50): 0. 15 microM) and pancreatic lipase (IC(50): 120 microM). The effects of the optically pure DU-6622 isomers on the two enzymes were compared. The (2R, 3R)-isomer was shown to be a highly specific inhibitor of HMG-CoA synthase (IC(50): 0.098 microM vs 270 microM for pancreatic lipase), while the (2S, 3S)-isomer markedly increased the specificity of lipase inhibition (IC(50): 27 microM vs 31 microM for HMG-CoA synthase). Furthermore, the (2R, 3R)-isomer strongly inhibited the binding of [(14)C]hymeglusin to HMG-CoA synthase, indicating that the isomer was bound to the same site of the synthase as hymeglusin. The (2R, 3R)-beta-lactone is responsible for the specific inhibition of HMG-CoA synthase, while the (2S, 3S)-beta-lactone is responsible for the inhibition of pancreatic lipase.

Animals↗
PubMed1997

Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety.

Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by gamma-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC50 values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition.

Enzyme Inhibitors↗