Biomedical subjects

T Kurihara

Publications and source records attributed to T Kurihara.

At least 505 records · Page 28Linked to original sources

PubMedDate not supplied

Quantumchemical structure of carcinogenic benz[c]acridines.

Resonance energies, circuit resonance energies and bond currents of benz[c]acridines were calculated by Aihara's IRE theory. Consequently, it was shown that these compounds had very stable aromatic characters with positive resonance energies and that the resonance energies per pi-electron values for the compounds with lack of the double bond corresponding to the K-region from parent skeleton were more stable than those of their parent compounds. Carcinogenic activity of the compounds was related to the charge at QK, QN and QL and high electron density on HOMO orbital.

Acridines↗

PubMedDate not supplied

Role of eicosapentaenoic acid in lipid metabolism in the liver, with special reference to experimental fatty liver.

Choline-deficient feed was given to three groups (n = 7 in each) of male Sprague-Dawley rats for 4 weeks to induce the development of fatty liver. In addition, two of the groups received eicosapentaenoic acid (EPA), 1000 mg/kg/d, administered orally either for all 4 weeks or for only the last 2 weeks of the study, respectively. The third group received the choline-deficient diet but no EPA. The untreated control group (n = 7) received only normal feed. The efficacy of EPA in preventing fatty liver was assessed based on the evaluation of pathologic and biochemical parameters and hepatic blood flow. EPA markedly improved fatty liver, probably due to both direct effects (inhibition of the synthesis of triglyceride in the liver) and indirect effects (increased hepatic blood flow). Decreased blood flow due to sinusoidal block is responsible for the progression of fatty liver. EPA has been shown to decrease thromboxane A2 production and blood viscosity and to enhance red cell deformability. These effects are thought to have contributed to the increases in hepatic blood flow.

Animals↗

PubMedDate not supplied

Inhibitory effect of ursodeoxycholic acid on the progression of chronic hepatic disorders with special reference to increases in blood flow.

Ursodeoxycholic acid (UDCA), which is commonly used as a cholesterol-gallstone-dissolving agent, is now expected to be effective not only for primary biliary cirrhosis but for chronic active hepatitis as well. In this study, we administered 0.1% ethionine-added, choline-deficient diet for 8 weeks to male Sprague-Dawley rats to prepare an animal model of chronic hepatic disorders. At the same time, UDCA (50 mg/kg/day) was administered orally to these animals, and its effects on the liver, including effects on hepatic blood flow determined with a laser Doppler blood flow meter, were evaluated. Hepatic blood flow increased significantly in the UDCA group compared with the untreated groups. Transaminase levels decreased significantly in the UDCA group compared with the untreated group. Histologic differences were noted between the UDCA and untreated groups in histopathologic examinations of the liver, with liver cirrhosis or early liver cirrhosis being present in the untreated group, compared with only chronic active hepatitis in the UDCA group. These findings suggest that UDCA is able to prevent or inhibit the progression of chronic hepatic disorders, an effect that may be due in part to increases in hepatic blood flow.

Alanine Transaminase↗

PubMedDate not supplied

Experimental use of pravastatin in patients with primary biliary cirrhosis associated with hypercholesterolemia.

Primary biliary cirrhosis (PBC) is a refractory liver disease for which no medical treatment has been established. The investigators administered 20 mg/day of pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, to 2 PBC patients with hypercholesterolemia (1010 and 306 mg/dl) for 3 years and 10 months in order to decrease the blood concentration of bile acids and prevent adverse effects on the hepatocellular membrane. The drug markedly decreased not only cholesterol levels but also total bile acid levels, producing particularly pronounced decreases in cholic acid and chenodeoxycholic acid. Histologically, progression was inhibited in one patient, whereas improvement was seen in the other. Bile duct enzymes and other biochemical parameters showed improvement in both cases. General pruritus and blepharal and palmar xanthoma also improved. These findings suggest that pravastatin may be useful in the treatment of PBC associated with hypercholesterolemia.

Biopsy↗

PubMedDate not supplied

Antiplasmid and carcinogenic molecular orbitals of benz[c]acridine and related compounds.

Effect of K- and L- molecular orbital regions on expression of antiplasmid and carcinogenic activity was studied with various benz[c]acridine derivatives, tricyclic compounds (acridine orange, phenothiazines) and dibenzoazepine (imipramine). Antiplasmid compounds showed the out-of-phase of molecular orbital in the L-region. On the other hand, mutagenic and carcinogenic compounds showed the out-of-phase in the L-region, and their energy was accumulated in the K-region of the molecular orbitals. The present study suggests that the molecular orbitals responsible for the expression of antiplasmid and carcinogenic effects might be basically different.

Acridines↗

PubMedDate not supplied

Immunomodulation activity of phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

Some non-differentiation-induction benzo[a]phenothiazines and mutagenic benz[c]acridines more potently inhibited the mitogen-induced blast transformation of human-peripheral blood lymphocytes than differentiation-induction and non-mutagenic counterparts and phenothiazines. Differential absorption spectrophotometry revealed tight complex formation between these drugs and bacterial endotoxin or mitogens. All of these compounds only slightly affected antibody dependent cellular cytotoxicity and natural killer cell activity, but significantly inhibited the endotoxin-or heat-killed Staphylococcus aureus induced tumor necrosis factor production by human mononuclear cells. Pretreatment of mice with these drugs protected them from lethal E. coli infection. Quantumchemical analysis suggests a correlation between the biological activity of these compounds and some molecular orbital parameters such as the charge at C7, and the ratio of polar/total surface areas.

Acridines↗

PubMedDate not supplied

Relationship between resonance energy per pi-electron and carcinogenicity in arenes.

The resonance energy per pi-electron of various arenes was calculated using Aihara's TRE theory. There seemed to be a correlation between the resonance energy volume per pi-electron of the cation species (lacking a carbon atom) with the highest approximate superdelocalizability (Sr'(E)) from the parent skeleton and carcinogenicity, i.e. the induction of cancer by arenes (three-ring, four-ring, five-ring, six-ring and seven-ring) seems to be dependent on the resonance energy per pi-electron in they contain).

Carcinogens↗

PubMedDate not supplied

Synthesis and antitumor activity of 1-[2-(chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl- 1-urea s as potent anticancer agents.

10-[N-(Phthalimido)alkyl]-2-substituted-10H-phenothiazines and 1-(2-chloroethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1- ureas were synthesized and found to have antiproliferative effects on human HEp-2 and L5178Y cell cultures. The multi-drug resistant subline of mouse lymphoma was sensitive to the reversal effects of some 10-[N-(phthalimido)alkyl]-2-substituted-10H-phenothiazines, while 1-(2-chloro-ethyl)-3-(2-substituted-10H-phenothiazin-10-yl)alkyl-1 -ureas were less effective but had a similar degree of antiproliferative effect on both cell lines.

Animals↗

PubMedDate not supplied

Correlations between topological resonance energy of methyl-substituted benz[c]acridines, benzo[a]phenothiazines and chrysenes, and their carcinogenic or antitumor activities.

In order to clarify the effects of methyl substitution on the carcinogenic activity, each resonance energy (RE) of benz[c]acridines, benzo[a]phenothiazines, chrysene, and their methyl derivatives was calculated by Aihara's TRE theory. Some correlations seem to exist between the values of resonance energy per pi-electron for the cationic species-with the lack of the atom having the highest approximate superdelocalizability (Sr'(E)) from their parents skeleton-and carcinogenic activity.

Acridines↗

PubMedDate not supplied

Relationship between resonance energy and carcinogenicity of azaarenes.

Resonance energy per pi-electron (REPE) of azaarenes were calculated by Aihara's theory of resonance energy (TRE). Consequently, it was shown that the REPE values for the cationic species not having the carbon, or nitrogen atom with the highest approximate superdelocalizability (Sr'(E)) in the parent skeleton were more unstable than those of their parent skeleton. Some correlations seem to exist between the REPE values for the cationic species not having the atom with the highest value of (Sr'(E)) in parent skeleton and carcinogenic activity. Other types of correlations can be assumed in the case of carbazoles 7H-benzo[g]pyrido[2,3-a]carbazole (14), 13H-dibenzo[a]pyrido[3,2-i]carbazole (17), and 7H-benzo[c]pyrido[2,3-g]carbazole (20) although there are some exceptions, i.e., 7H-benzo[g]pyrido[3,2-a]carbazole (15) and 7H-dibenzo[c,g]-carbazole (18). The bond-order affected carcinogenicity induction in some ways as well.

Acridines↗

PubMedDate not supplied

Radical intensity and differentiation-inducing activity of benzo[a]phenothiazines and phenothiazines.

ESR spectroscopy revealed that 12H-benzo [a]phenothiazine, 9-methyl-12H-benzo[a]phenothiazine, 10-methyl-12H-benzo [a]phenothiazine, 11-methyl-12H-benzo[a]phenothiazine and 5-axo-5H-benzo[a]phenothiazine, which induced the differentiation of human myelogenous leukemic cell lines into maturing macrophages, produced radical(s) under an alkaline condition. On the other hand, 6-hydroxy-5-axo-5H-benzo [a]phenothiazine, 6-methyl-5-oxo-5H-benzo[a]phenothiazine and 5H-benzo[a][1,4]benzothiazino-[3,2-c]phenothiazine, and 13 phenothiazines, which had little or no differentiation-inducing activity, produced no detectable amounts of radical(s). Using Hückel molecular orbital (HMO) method, these active benzo[a]phenothiazines were shown to have the elevated n-spin density at the sulfur atom of their molecules. Seven out of 8 benzo[a]phenothiazines significantly enhanced the radical intensity of sodium L-ascorbate and sodium 5,6-benzylidene-L-ascorbate (SBA), whereas only 3 out of 13 phenothiazines showed similar effects. These data suggest that the induction of human leukemic cell differentiation by benzo[a]phenothiazines might be initiated by radical mediated reactions.

Cell Differentiation↗

PubMedDate not supplied

Relationship between biological activity and dipole moment in benzo[a]phenothiazines.

Relationship between the biological activity and two different dipole moments were investigated in 9 benzo[a]phenothiazines [1-8] by calculating the dipole moment with the PM3 method. 12H-Benzo[a]phenothiazine [1], 9-methyl-12H-benzo[a]phenothiazine [2], 10-methyl-12H-benzo[a]phenothiazine[3] and 11-methyl-12H-benzo[a]phenothiazine [4] induced monocytic differentiation of human myelogenous leukemic cell lines and displayed antitumor activity. These active compounds showed a significantly smaller value of calculated ground-state dipole moment (mu g) and larger value of first excited-state dipole moment (mu e). The mu e/mu g ratio of four active compounds [1-4] ranged from 3.25 to 4.38, whereas that of three inactive compounds [5,6,7] ranged from 1.77 to 2.72. These two different dipole moments might be useful parameters for estimation of the biological activity of benzo[a]phenothiazines [1-8].

Animals↗

PubMedDate not supplied

Drug resistance reversal, anti-mutagenicity and antiretroviral effect of phthalimido- and chloroethyl-phenothiazines.

The effect of substituted phenothiazines was studied in three different systems; bacteria and cancer cells and reverse transcriptase enzyme of Moloney leukemia virus. F'lac and hemolysin plasmids were eliminated by some substituted phenothiazines from E. coli at a very low frequency. The same phenothiazine derivatives also were synergistic with tetracycline in bacteria and shown antimutagenic effect in Ames test. No mutagenic effects were observed in TA 98 strain of Salmonella typhimunium. Chloroethyl-substituted phenothiazines showed antimutagenicity equivalent to the parent compounds; however, phthalimido-substituted phenothiazines had higher antimutagenicity of 50%. P-glycoprotein responsible for multidrug resistance was also inhibited in tumor cells. The accumulation of the fluorescent rhodamine 123 in the phenothiazine treated multi-drug resistant tumor cells was measured by flow cytometry. Some of the substituted phenothiazines were effective P-glycoprotein blockers, while some compounds had moderate activity, but others were without effect as compared to 5 microM verapamil. On the basis of computer analysis there are some correlations between the biological activities and the dipole moments, and entropy of the studied molecules. Our results suggest that the inhibition of Hly+ plasmid replication and P-glycoprotein function may depend partly on similar electronic properties of the studied phenothiazine derivatives. The activity of Moloney leukemia virus reverse transcriptase was inhibited by the substituted phenothiazines, however, no basic differences were found in the activities of phthalimido- and chloroethyl substituted phenothiazines.

Antimutagenic Agents↗

PubMedDate not supplied

Radical intensity and carcinogenic activity of benz[c]acridines.

Among 13 benz[c]acridines, six 7-methyl-substituted compounds (7-methylbenz[c]acridine, 7,9-dimethylbenz[c]acridine, 7,10-dimethylbenz[c]acridine, 7,11-dimethylbenz[c]acridine, 7,9,10-trimethylbenz[c]acridine, 7,9,11-trimethylbenz[c]acridine) were carcinogenic, while the other seven compounds (benz[c] acridine, 8-methylbenz[c]acridine, 9-methylbenz[c]acridine, 10-methylbenz[c]acridine, 11-methylbenz[c]acridine, 5,7-dimethylbenz[c]acridine, cis-5,6-dihydroxy-5,6-dihydrobenz[c]acridine) were inactive. Using both McLachlan-Hückel molecular orbital (McLachlan-HMO) and HMO methods, all the carcinogenic compounds were shown to have the elevated pi-spin density at 12th nitrogen atom of their molecules, as compared with noncarcinogenic compounds. Electron spin resonance (ESR) spectroscopy, however, revealed that both carcinogenic and noncarcinogenic compounds produced no detectable amounts of radical. This is in contrast to ascorbates, gallates and benzo[a]phenothiazines, which induced apoptosis by radical mediated mechanism(s). Amino acid analysis demonstrated that methionine oxidation is not involved in the induction of carcinogenic activity by benz[c]acridines.

Acridines↗

PubMedDate not supplied

Correlation between structure and diverse biological activities of "half-mustard type" phenothiazines.

The structure and activity relationship of fifteen "half-mustard type" phenothiazines and related compounds were investigated. These compounds did not show any direct bactericidal activity, possibly due to the lack of radical generation activity. Pretreatment with phenothiazines significantly reduced the lethality of Escherichia coli GN2411 infection, possibly due to activation of the host defense mechanism. Higher concentrations of these compounds showed cytotoxic activity against several cultured tumor cell lines. However, no clear-cut relationship was established between biological activity and two dipole moments (mu g, mu e).

Anti-Bacterial Agents↗

PubMedDate not supplied

Biological activity of 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones.

Ten 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones (Coumarins)[1-7] and related coumarins [8-10] were compared for their cytotoxic activity and radical intensity. Among these compounds, compound 7 showed highest cytotoxic activity against human promyelocytic leukemic HL-60 cells. Compound 7 produced radicals under alkaline conditions, and showed the lowest pi-spin density at S-atom of the molecule, suggesting the delocalization of pi-spin density. These data suggest the possible relation between radical intensity and biological activity.

Antineoplastic Agents↗

PubMedDate not supplied

Radical productions and pi-spin density by UHF/PM3 method on benz[c]acridines and benzo[a]phenothiazines.

On the calculated pi-spin density (rho pi) of benz[c]acridines [1-12], benz[c]acridines [2,8-12] with alternately value of pi-spin density (rho pi) on angular ring, large negative pi-spin density at C-1 and C-3 positions and large positive pi-spin density at C-2 and C-4 positions indicates their carcinogenicity, except for 7-methylbenz[c]acridine [7]. Benz[c]acridines [1,3-6] which do not follow were not carcinogenic. Radical producing benzo[a]phenothiazines [13-16] and non-radical producing benzo[a]phenothiazines [17-19] gave calculated pi-spin density (rho pi) which was positive in radical producing benzo[a]phenothiazines [13-16] at N-12 position, and had the opposite pi-spin density in non-radical producing benzo[a]phenothiazines [17-19].

Acridines↗

PubMedDate not supplied

Relationship between radical intensity and cytotoxic activity of dopamine-related compounds.

Millimolar concentrations of dopamine (DA), norepinephrine (NE), and 3,4-dihydroxyphenylacetic acid (DOPAC) were cytotoxic to human promyelocytic leukemiC HL-60 cells. However, their metabolites (3,4-dihydroxymandelic acid (DOMA), 3-methoxytyramine (MT), normetanephrine (NMN)) and six synthetic derivatives (which have two OCH3 groups replacing two OH groups on catechol backbone) displayed much lower cytotoxic activity. Three active compounds, but not other less potent compounds, produced radicals under alkaline conditions. All active compounds significantly enhanced the decay of ascorbic acid endogenously present in rat brain homogenate, whereas all synthetic derivatives were inactive. Ascorbic acid induced apoptotic cell death in HL-60 cells and the apoptosis induction was significantly reduced by simultaneous addition of (DA). The cytotoxic activity of (DA) was also neutralized by ascorbic acid. These data suggest the possible interaction between (DA) and ascorbic acid.

Animals↗