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YAKUGAKU ZASSHI, 121(12),845-873, 2001
A small knowledge base was created by organizing the Human Genome Project (HGP) and its related issues in “Science” magazines between 1996 and 2000. This base revealed the stunning achievement of HGP and a private venture and its impact on today's biology and life science. In the mid-1990, they encouraged the developement of advanced high throughput automated DNA sequencers and the technologies that can analyse all genes at once in a systematic fashion. Using these technologies, they completed the genome sequence of human and various other organisms. These fruits opened the door to comparative genomics, functional genomics, the interdisprinary field between computer and biology, and proteomics. They have caused a shift in biological investigation from studying single genes or proteins to studying all genes or proteins at once, and causing revolutional changes in traditional biology, drug discovery and therapy. They have expanded the range of potential drug targets and have facilitated a shift in drug discovery programs toward rational target-based strategies. They have spawned pharmacogenomics that could give rise to a new generation of highly effective drugs that treat causes, not just symptoms. They should also cause a migration from the traditional medications that are safe and effective for every members of the population to personalised medicine and personalised therapy.
Key words--knowledge base; Science magazine; Human Genome Project; completion of human genome sequencing, genomics and proteomics; drug discovery and therapy
YAKUGAKU ZASSHI, 121(12),875-885, 2001
The brain includes glial cells (astrocytes, microglia and oligodendrocytes) and endothelial cells in addition to neurons. Under some pathological conditions, it is invaded by leukocytes such as neutrophils, monocytes/macrophages and lymphocytes. Intercellular communication across these cell species is supposed to play crucial roles both in the brain functions and dysfunctions. However, the molecular basis of such intercellular communication remains unclear. We have studied the roles of cytokines and chemokines, which have been investigated as essential mediators in the immune and inflammatory systems, in intercellular communication across neurons, glial cells, endothelial cells and leukocytes. Messenger RNA expression of cytokines such as interleukin-1β was induced in brain microglia by i.p. injection of excitotoxin and neurostimulant, at least, partly via catecholaminergic systems. Messenger RNA of other cytokines such as leukemia inhibitory factor was induced in astrocytes. This cytokine specifically induced nociceptin mRNA in the cultured cortical neurons. Constitutive expression of some chemokines such as fractalkine and stromal cell derived factor-1α was observed in the brain, suggesting that they play important roles in maintenance of brain homeostasis or determination of the patterning of neurons and/or glial cells in the developing and adult brains. Cytokines such as interleukin-1β and chemokines such as monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α were produced in ischemic brain and implicated in ischemic brain injury. In addition to ischemia, cytokines, chemokines and their receptors have been shown to be involved in various neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease and AIDS dementia syndrome. They are potential targets for therapeutic intervention for neurodegenerative diseases.
Key words--cytokine; chemokine; brain; ischemia; astrocyte; microglia
YAKUGAKU ZASSHI, 121(12),887-898, 2001
Intramolecular cascade reaction has received much attention as a powerful methodology to construct a polycyclic framework in organic synthesis. We have been developing “boomerang-type cascade reaction” to construct a variety of polycyclic skeletons efficiently. In the above reactions, a nucleophilic function of substrates changes the character into an electrophile after the initial reaction, and the electrophilic group acts as a nucleophile in the second reaction. That is, the reaction center stepwise moves from one functional group back to the same one via other functional groups. The stream of the electron concerning the cascade reaction is like a locus of boomerang. We show here three different boomerang-type reactions via ionic species or free radicals. 1) Diastereoselective Michael-aldol reaction based on the chiral auxiliary method and enantioselective Michael-aldol reaction by the use of external chiral sources. 2) Short and efficient total syntheses of longifolane sesquiterpenes utilizing intramolecular double Michael addition as a key step. 3) Development of boomerang-type radical cascade reaction of halopolyenes to construct terpenoid skeletons and its regioselectivity.
Key words--cascade reaction; selective synthesis; polycyclic systems; ionic reaction; radical reaction; culmorin
YAKUGAKU ZASSHI, 121(12),899-908, 2001
Studies on the cellular and molecular mechanism of neurotransmitter receptor-signaling and of neuronal and glial cell responses to stresses seem to be important to elucidate the action mechanism of centrally-acting drugs and to develop novel therapeutics against several diseases in the brain. The present review shows our findings with regard to the membrane receptor-signaling mechanism including serotonin, noradrenaline, glutamate receptors, ion channels, G-proteins, protein kinases and drug actions in Xenopus oocytes injected with rat brain mRNA, NG108-15 cells and brain membranes. Regarding the results of studies on the inter- and intra-cellular mechanism of neurons and glial cells against cerebral ischemia/hypoxia, we review the involvement of a transcription factor NF-κB in LPS-elicited inducible NO synthase (iNOS) expression in rat astroglial cells. Then we describe possible involvement of: 1) ADP-ribosylation/nitrosylation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and 2) decrease in mitochondrial membrane potential, release of caspase-3 from mitochondria and degradation of the inhibitor of caspase-activated DNase by activated caspase in NO-induced neuronal apoptosis. We observed that hypoxia results in expression of a molecular chaperon such as protein disulfide isomerase (PDI) and HSP70 in astroglial cells. Our recent findings indicate that overexpression of PDI in the rat hippocampus (in vivo) and in neuroblastoma SK-N-MC cells (in vitro) significantly suppress the hypoxia-induced neuronal death. From physiological/pathophysiological and pharmacological aspects, we review the importance of studies on the cellular and molecular mechanism of membrane receptor-signaling and of stress-responses in the brain to identify functional roles of neuro-glial- as well as neuro-neuronal interaction in the brain.
Key words--neurotransmitter; membrane receptor-signaling; apoptosis; brain ischemia; neuron-glia; drug action
YAKUGAKU ZASSHI, 121(12),909-914, 2001
Clinical studies have demonstrated that when opiates are used to control cancer pain, psychological dependence and analgesic tolerance are not a major concern. The present study was, therefore, designed to investigate the modulation of rewarding effects of opiates under inflammatory chronic pain in SD rats. Formalin (2.5%, 50 μl) or carrageenan (1%, 100 μl) was injected into the plantar surface of the rat paw. Formalin and carrageenan reduced the paw pressure threshold. The hyperalgesia lasted for 9 to 13 days. Rewarding effect of morphine was evaluated by conditioned place preference paradigm. Morphine produced a significant place preference. This effect was significantly attenuated in inflamed groups as compared with the respective non-inflamed groups. Furthermore, the morphine-induced place preference in the inflamed group gradually recovered to the respective control level as the inflammation healed. On the other hand, we found that κ-opioid receptor agonists markedly inhibit rewarding effect of μ-opioid receptor agonists. Therefore, to elucidate the mechanism of this attenuation, the effects of pretreatment with κ- and δ-opioid receptor antagonists, nor-binaltorphimine (nor-BNI) and naltrindole (NTI), on the development of the morphine-induced place preference under inflammation were examined. Nor-BNI, but not NTI, eliminated the suppression of the morphine-induced place preference in inflamed groups. The morphine-induced increase in dopamine turnover in the limbic forebrain was suppressed under inflammation, and the suppression was abolished by the pretreatment with nor-BNI. These results suggest that endogenous κ-opioid systems may be activated by chronic inflammatory nociception, resulting in the suppression of the development of rewarding effects produced by morphine.
Key words--morphine; inflammatory nociception; rewarding effect; opioid receptor; dopamine
YAKUGAKU ZASSHI, 121(12),915-927, 2001
An orally active penem antibiotic, Farom (generic name: faropenem), was designed by the conformational analysis of active and inactive penem derivatives. Faropenem showed potent activity against a wide variety of bacteria including extended-spectrum β-lactamase (ESBL)-producing ones. The mechanism of the stability against ESBL was elucidated by modeling the Michaelis complex of faropenem and Toho-1, an ESBL. Modeling of a complex of faropenem at the active site of a penicillin-binding protein 2 (PBP2) model suggested the characteristic affinity for faropenem with PBP2 of Escherichia coli. Faropenem has been totally synthesized from (R)-1,3-butanediol. The synthetic intermediate, a 3-hydroxyethyl-4-acetoxyazetidinone derivative, was efficiently prepared by the 2+2 coupling of a optically active vinylsulfide derivative and chlorosulfonyl isocyanate, followed by the substitution of the acetoxy group for the thiophenyl group at the C-4 position.
Key words--penem; β-lactam antibiotic; orally active; β-lactamase; penicillin-binding protein
YAKUGAKU ZASSHI, 121(12),929-948, 2001
Peptide and protein drugs are becoming a very important class of therapeutic agents. However, the oral bioavailability of peptide and protein drugs is generally poor because they are extensively degraded by proteases in the gastrointestinal tract or impermeable through the intestinal mucosa. For the systemic delivery of the peptide and protein drugs, parenteral administration is currently required to achieve their therapeutic activities. However, this administration is poorly accepted by patients and may cause allergic reactions and serious side effects. Therefore, various approaches have been examined to overcome the delivery problems of these peptides when they are administered into the gastrointestinal tract and other mucosal sites. These approaches include (1) to use additives such as absorption enhancers and protease inhibitors, (2) to develop an administration method for peptides that can serve as an alternative to oral and injection administration, (3) to modify the molecular structure of peptide and protein drugs to produce prodrugs and analogues, and (4) to use the dosage forms to these peptide drugs. In this study, we demonstrated that the transmucosal absorption of various peptides including insulin, calcitonin, tetragastrin and thyrotropin releasing hormone (TRH) could be improved by the use of these approaches. Therefore, these approaches may give us basic information to improve the transmucosal absorption of peptide and protein drugs.
Key words--drug absorption; transmucosal absorption; peptide drug delivery; absorption enhancer; colon-specific drug delivery; pulmonary absorption
YAKUGAKU ZASSHI, 121(12),949-960, 2001
The design, synthesis, and application of a new bifunctional enantioselective catalyst containing both Lewis acidity and Lewis basicity are described. Recent developments of chiral quaternary stereocenter synthesis through catalytic enantioselective Reissert-type reaction and cyanosilylation of ketones forming the S-enantiomer are chiefly reviewed. The catalysts are composed of a Lewis acid metal (aluminum, titanium, or lanthanide) and a Lewis base (the oxygen atom of a phosphine oxide), of which positions are defined by 2,2'-binaphthol (BINOL) or a carbohydrate scaffold. Utilizing these catalysts, we have developed a variety of enantioselective cyanation reactions, such as cyanosilylation of aldehydes and ketones, Strecker-type reaction, and Reissert-type reaction. These reactions showed a broad substrate generality. Investigations toward the elucidation of the reaction mechanism, involving kinetic studies, comparison of the results by control catalysts, and absolute configurations of the products, revealed that these reactions are catalyzed by a dual activation of a substrate and trimethylsilyl cyanide (TMSCN) by the Lewis acid and the Lewis base of these catalysts. Catalytic enantioselective synthesis of several drug lead compounds, such as anti-cancer epothilones, potent N-methyl-D-aspartate (NMDA) receptor antagonists, phenytoin analogs, salsolinol carboxylic acid, and anti-cancer camptothecin was achieved, using these reactions as key steps.
Key words--bifunctional catalyst; enantioselective reactions; drug lead; BINOL; sugar; dual activation
YAKUGAKU ZASSHI, 121(12),961-969, 2001
A nickel(0)-catalyzed asymmetric [2+2+2] cocyclization has been realized for the first time. This reaction involves conceptually new enantiotopic group selective formation of a nickelacyclopentadiene intermediate and produces an isoindoline derivative (73% ee, 78% conv. yield) and an isoquinoline derivative (54% ee, 62% yield) having benzylic chiral carbon centers. The synthesizing methods of biaryls using the nickel-catalyzed [2+2+2] cocyclization were also developed. Two ways for the synthesis of biaryl using [2+2+2] cocyclization were investigated: one method is that biaryls synthesized from alkyne having a phenyl group and 2 equivalents of acetylene, and the other method is that those were synthesized from α,ω-diyne having a phenyl group at the α-position and acetylene.
Key words--nickel; [2+2+2] cocyclization; asymmetric synthesis; acetylene; cyclization; biaryl
YAKUGAKU ZASSHI, 121(12),971-988, 2001
This review summarizes our studies on the development of the syntheses of cyclazine derivatives. These studies involve the following four main subjects; 1) the studies on cycl [3.2.2] azine derivatives; 2) the studies on cycl [3.3.2] azinone derivatives; 3) the studies on azacycl [3.3.3] azine derivatives; 4) the studies on cyclazinophane derivatives.
Key words--cycl [3.2.2] azine; cycl [3.3.2] azinone; azacycl [3.3.3] azine; cyclazinophane
YAKUGAKU ZASSHI, 121(12),989-994, 2001
The transport mechanisms of the enantiomers of BOF-4272, a new drug for the treatment of hyperuricemia, were studied using freshly prepared rat hepatocytes. BOF-4272 consists of S (−) and R (+) enantiomers due to a chiral center in the sulfoxide moiety. The uptake of these BOF-4272 enantiomers by hepatocytes was found to be temperature and dose dependent. The temperature-dependent uptake of the S (−) and R (+) enantiomers showed saturation kinetics. The Km values for the S (−) and R (+) enantiomers were 59.3 and 25.7 μ, respectively, which was a significant difference (p< 0.05). However, the maximal uptake rate was comparable for both enantiomers. Metabolic inhibitors such as antimycin, oligomycin, rotenone, carbonylcyanide m-chlorophenyl hydrazone, and carbonyl cyanide-p-(trifluromethoxy)-phenylhydrazone significantly inhibited uptake of the R (+) enantiomer, but had little effect on uptake of the S (−) enantiomer. Ouabain (an inhibitor of Na+/K+-ATPase) and p-nitrobenzylthioinosine (NBMPR, a nucleoside transporter inhibitor) showed no significant effects on the uptake of either enantiomer. Organic anions such as taurocholate and cholate reduced the uptake of both enantiomers. These results suggest that the hepatic uptake of both BOF-4272 enantiomers is not due to simple diffusion but also involves carrier-mediated uptake. We suggest that the carrier-mediated uptake of BOF-4272 enantiomers includes both NBMPR-insensitive facilitated diffusion and an active transport system in liver plasma membrane, and that the enantioselective uptake of BOF-4272 is due to differences in affinity for the active transporter.
Key words--enantioselective uptake; xanthine oxidase inhibitor; chiral sulfoxide; hepatocytes; BOF-4272
YAKUGAKU ZASSHI, 121(12),995-1004, 2001
In the Department of Obstetrics and Gynecology at our hospital, a team of doctors, pharmacists, nurses, and other medical staff was established to prepare a clinical pathway for laparoscopic cystectomy. Various data on clinical charts including the use of drugs were collected from 57 patients by pharmacists and nurses. Based on the analysis of these data, hospitalization period, method of preoperative bowel preparation, time to initiation of food intake, duration of antibiotic administration, and time and content of pharmaceutical instructions to patients of dosage and administration were determined. Criteria for variances requiring the doctor' s directions were determined for fever, wound pain, and vomiting. The clinical pathway established here allows of not only the efficient and uniform care of patients, but also the active exchange of opinions among members of the medical team. Moreover, most patients who replied to a questionnaire said that they were at ease during hospitalization because they had received detailed information about the clinical pathway including the use of drugs before surgery. Thus, the participation of pharmacists on a medical team that is introducing a clinical pathway is particularly important because the use of drugs and pharmaceutical care are an important part of good patient care.
Key words--clinical pathway; laparoscopic cystectomy; medical team; pharmacist; variance
YAKUGAKU ZASSHI, 121(12),1005-1010, 2001
Preparative constant-current electrolysis of N, N-dimethylaniline (100 mM, DMA) was carried out in dry acetonitrile containing Et4NClO4 to give N, N, N', N'-tetra-methylbenzidine (TMB) and 4,4'-methylenebis(N, N-dimethylaniline) (MDMA). In the presence of HCl, DMA was quantitatively oxidized to TMB. Formation mechanism of MDMA was discussed using the results of semi-empirical calculations that were PM3 and AM1. The proposed mechanism by Hand and coworker was ruled out and an alternative one is suggested as follows. DMA undergoes one-electron oxidation at the anode and gives the corresponding N, N-dimethylaniline cation (A). Aydroxy ion, instead of DMA, abstracts a proton from A and gives H2O and methyl(phenyl) aminomethyl radical (B). B reacts with DMA to give a 1-dimethylamino-4-(N-methyl-N-phenylamino) methyl-2,5-cyclohexadienyl radical (I). The radical I decomposes to N-methylaniline and a 1-dimethylamino-4-methylene-2,5-cyclohexadienyl radical (J). The radical J reacts with DMA to give a 1-dimethylamino-4-(4-dimethylaminobenzyl)-2,5-cyclohexadienyl radical (K), which is oxidized to MDMA by the anode.
Key words--anode; oxidation; N, N-dimethylaniline; electrolysis; PM3; AM1