Mechanisms of metabolic activation of carcinogenic chemicals, especially arylamines, are discussed together with characteristics of enzymes involved in the activation in the liver and extrahepatic tissues. In rodents, drug and carcinogen metabolizing activities often show clear age-and sex-related differences and also vary in diseased states. The current understanding of the roles of pituitary growth hormone and thyroid hormone on changes of hepatic drug metabolizing enzymes is shown in relation to the developmental changes and alteration in patho-physiological conditions.
A new concept of cyclic conjugation as a modification of the Huckel rule has proven to be useful as a general method for predicting thermal stabilities and electronic properties of unsaturated cyclic organic molecules. We have been applying this concept to the design of reagents such as p-benzoquinone, polyquinones, and 1, 4-dithiins. Our efforts for the molecular design have relied extensively on the use of pericyclic reactions as pivotal steps in the total synthesis of polycyclic natural products incorporating fused heterocyclic subunits, targets that traditionally have provided fertile grounds for the development of new synthetic strategies. In order to obtain a quantitative understanding of the linkage between drug-bioreceptor complex formation, we have investigated the design and synthesis for the biologically active compounds (receptor probes) as follows : 1) the design and structure-activity relationship of a series of S-activated opioid agonist and antagonist ligands, 2) the design and synthesis of crowned morphine as the opioid receptor probes and 1, 4-benzoquinones as ionophore-dienophile combined systems, 3) synthesis of the base stacking and hydrogen-bonded nucleic acid base pair.
New quaternary ammonium salts [N-alkyl-N-2-hydroxyethyl-N, N-dimethylammonium ethyl phosphate (21, 22), isopropyl phosphate (23), n-butyl phosphate (24) and N-alkyl-N-2-hydroxy-3-phenoxypropyl-N, N-dimethylammonium ethyl phosphate (25, 26), isopropyl phosphate (27), n-butyl phosphate (28) and bis(N-alkyl-N-2-hydroxy-3-phenoxypropyl-N, N-dimethylammonium) malate (29), fumalate (30), succinate (31), adipate (32) and N-alkyl-N-2-hydroxy-3-phenoxypropyl-N, N-dimethylammonium tartarate (33)] were synthesized by alkylation of the corresponding trialkylammonium salts with various epoxy compounds. The new quaternary ammonium salts showed much greater bactericidal activities and antirusting effects than those of benzalkonium chloride. They had also good compatibilities since no precipitate was observed if the solution of any anionic surface active agents were added to the solution of these new quaternary ammonium salts. This property is the same as that of amphoteric surface active agents.
A series of 3-O-alkyl and 3-O-haloalkyl-o-glucoses were prepared from 1, 2 : 5, 6-di-O-isopropylidene-α-D-glucofuranose and their antibacterial activities were evaluated. The compounds with C12 and C14-alkyl chains were the most effective in vitro antibacterial screening, among 3-O-alkyl and 3-O-haloalkyl derivatives. The 3-O-alkyl derivatives were more effective than 3-O-haloalkyl derivatives.
5, 6-Diphenyl-, 3, 5-diphenyl-, and 3, 6-diphenyl-1, 2, 4-triazine (as-triazine) derivatives were evaluated for inhibitory activity towards arachidonic acid-induced aggregation of rabbit blood platelet in vitro. Among the isomers, 5, 6-diphenyl-as-triazine derivatives were active, therefore a phenyl substituent on the as-triazine ring at the 5-and 6-position was essential for the inhibitory activity. Thus, various 3-substituted 5, 6-diaryl-as-triazines were synthesized by the nucleophilic substitution reaction of 5, 6-diaryl-3-methylsulfonyl-as-triazines with O, N, C-nucleophiles. In the case of as-triazines having different aryl groups at the 5-and 6-positions, the compounds were prepared by the stepwise addition reaction of Grignard reagents with 3-methylthio-as-triazine. Among these compounds, ethyl 5-(4-methoxyphenyl)-6-phenyl-as-triazine-3-acetate (24a) and ethyl 5, 6-bis(4-methoxyphenyl)-as-triazine-3-acetate (24f) showed the most potent inhibitory activity, which was almost equal to the activity of anitrazafen.
The transport properties of benzoic acid and its eighteen derivatives such as o-, m-or p-hydroxybenzoic acid (o-, m-or p-HBA), aminobenzoic acid (o-, m-or p-ABA), toluic acid (o-, m-or p-TA), fluorobenzoic acid (o-, m-or p-FBA), chlorobenzoic acid (o-, m-or p-CBA) and bromobenzoic acid (o-, m-or p-BBA) through human erythrocyte membranes were examined. The drugs having a hydrophilic ortho-substituent and those having a hydrophobic meta-or para-substituent showed higher transport. The ratio of free drugs in erythrocytes, fuR, did not relate to the partition coefficient (P). However, fuM (the ratio of free drugs in the plasma) and Kp. (the ratio of partition between erythrocytes and plasma) related to the P : fuM=-0.3128×log P+0.9727 (R2=0.8722***), Kp=-0.2558×log P+0.8642 (R2=0.8413***). In p-nitrophenol-glycosides, the fuM and the Kp that were predicted from these equations were compatible with the experimental results. It was suggested from these results that the fuM and the Kp may be predictable from the P.
Physicochemical characteristics of crystalline water of (RS)-7-(2-amino-methylmorpholino)-1-cyclopropyl-6, 8-difluoro-1, 4-dihydro-4-oxo-3-quinoline-carboxylic acid were studied by thermal analyses and powder X-ray diffractmetry. The dihydrate of the compound was stable under ambient or humidified conditions. The dihydrate converted to a monohydrate on drying under mild conditions. The mono-and dihydrates transformed into α-type anhydrate at 110°C. These three kinds of crystals were convertible each other under appropriate conditions. At 165°C, the hydrates and the α-anhydrate converted to β-type anhydrate. The compressed effects on the crystalline waters were also discussed for the dihydrate by kinetic analyses.
The significance of the stationary time of punch in the process of compression on the dividing properties of scored tablets was investigated in several tablets prepared from lactose, corn starch, hydroxypropyl starch, synthetic aluminum silicate, microcrystalline cellulose or Perfiller<【○!R】>. The dividing strength of scored tablets was not affected by the stationary time of punch. The effect of the stationary time of punch on the coefficient of variation of divided tablet weight differed in the compacting characteristics and compaction profiles of powders. In case of tablets prepared from microcrystalline cellulose, the effect of stationary time of punch was not observed. However, in the other excipients, there existed a specific stationary time of punch to minimize the coefficient of variation of divided tablet weight. The time was different due to the change of compression pressure. The coefficient of variation of divided tablet weight showed minimum at the longer stationary time of punch when tablets were compressed at the low compression pressure, and the time showed a tendency to become short with the increase of compression pressure. These results suggested that the effect of the stationary time of punch on the coefficient of variation of divided tablet weight was concerned with the compaction structure of powders produced by the movement of punch in the process of compression.
The effects of the oxyethylene chain length of poly(oxyethylene) hydrogenated castor oil (HCOn) on the micellar formation and on the micellar structure were investigated. Some physicochemical properties of HCOn(critical micelle concentration cmc, surface tension at cmc, free energy of micellization, and surface excess) concerning surface-activity were measured. These physicochemical properties were little affected by the oxyethylene chain length of HCOn. In addition, several physical techniques have been used to study the micellar structure of HCOn. It was found that HCOn. micelles were spherical or nearly spherical, and that an increase in the oxyethylene chain length led to an increase in the looseness of HCOn. micelle.
A series of 6-alkylaminopyridazine-3-carboxylic acid derivatives was tested for dopamine β-hydroxylase inhibitory activity in vitro according to the method of Kruse et al. Methyl 6-alkylaminopyridazine-3-carboxylates (4) were synthesized through the reaction of methyl 6-chloropyridazine-3-carboxylate (1) with ammonia followed by the condensation with primary amines, and by the methanolysis of the resulting 6-alkylaminopyridazine-3-carboxa-mides (3) in methanol in the presence of boron trifluoride etherate. Among tested compounds, 6-benzylaminopyridazine-3-carboxylic acid was found to have the most potent inhibitory activity, which was in the same level of the activity of fusaric acid.