Biomedical subjects
Publications and source records attributed to K Takeya.
A new guaiane sesquiterpenoid glycoside together with known sesquiterpenoids and iridoid glycosides have been isolated from the rhizomes and roots of Valeriana fauriei. The 13C NMR assignments of the isolated compounds are presented.
Cajucarinolide and isocajucarinolide, two new clerodane diterpenes, have been isolated from the cortices of Croton cajucara (Euphorbiaceae). These compounds possess anti-inflammatory activity and inhibit bee venom phospholipase A2 in vitro.
Using high-resolution proton nuclear magnetic resonance (1H-NMR) and carbon-13 nuclear magnetic resonance (13C-NMR) experiments, we have assigned three discernible configurational isomers observed in dimethyl sulfoxide-d6 (DMSO-d6) for an antitumor cyclic hexapeptide, RA-VII isolated from Rubia cordifolia. The largest isomer, amounting to 64%, has been assigned as conformer A with only a cis configuration between Tyr-5 and Tyr-6. The second configurational isomer, accounting for 32%, has adopted cis configurations between both Tyr-5 and Tyr-6 and between Ala-2 and Tyr-3. The third isomer, amounting to 4%, was determined to have cis configurations for all of the three N-methyl amide bonds.
Four new bicyclic hexapeptides, named as RA-XI, -XII, XIII and -XIV were isolated from Rubia cordifolia and showed potent antitumor activities against P-388. The structures were elucidated from spectroscopic and chemical evidences. RA-XII, XIII and -XIV were proved to be unique bicyclic hexapeptidic glucosides.
The methanolic extract of Swartzia polyphylla DC. heartwood had antibacterial activity against cariogenic bacteria, the mutans Streptococci. The chromatographic purification of the extract afforded seven flavonoids. Among them, three known isoflavanones, dihydrobiochanin A, ferreirin and darbergioidin, and one new isoflavanone, 5,2',4'-trihydroxy-7-methoxyisoflavanone (dihydrocajanin) had potent antibacterial activity against cariogenic bacteria. This effect was not detected on isoflavone derivatives. A comparative antibacterial study of various flavonoids was further performed, and their structure-activity relationship was discussed.
Metabolites of antitumor cyclic hexapeptides, RA-VII and -X which were isolated from Rubia cordifolia were studied by hepatic microsomal biotransformation in rats and in bile juice of rabbits to which these drugs were administered intravascularly. Their structures and conformations were elucidated by two-dimensional nuclear magnetic resonance techniques, temperature effect on NH protons and nuclear Overhauser effect experiments. Specific N-demethylation of Tyr-3, O-demethylation and hydroxylation at aromatic rings of Tyr-3 and -5 were observed. Compared with metabolites of RA-VII, most of RA-X was excreted unchanged in the bile juice. Relationship among their structures, conformations and antitumor activities is also discussed.
Three aromatic compounds (2-4) possessing a carbomethoxyl group or a dimethoxyphthaloyl group, prepared by the Diels-Alder reaction of the cardiac glycoside, proscillaridin (1), with dimethyl acetylenedicarboxylate and methyl propiolate, were transformed into alcohols, carboxylic acids and amides. The biological activities of the resulting derivatives were evaluated by the use of Na+, K(+)-adenosine triphosphatase (Na+,K(+)-ATPase) from dog kidney and isolated guinea-pig papillary muscle. Although the biological activities of the resulting derivatives were less potent than that of 1, a para-substituted benzylalcohol (5), methylbenzamides (9a and 10a), and ethylbenzamides (9b and 10b) inhibited the activity of Na+,K(+)-ATPase almost as potently as naturally occurring cardiac glycosides such as digoxin and digitoxin.
To reduce the vascular contracting effect of the hydrogenated cardiac glycosides, 20-(R)- and 20-(S)-tetrahydroproscillaridins (THPs, 1a, 1b), and to extend the concentration-dependent range, mono- and dinitrates of THPs were prepared. The pharmacological activities of the nitrates of THP were evaluated by use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase preparations from dog kidney. Furthermore, the effect for smooth muscle was examined using the helical strips isolated from 13-week-old spontaneously hypertensive rat. The positive inotropic effects of mononitrates (11a, 11b, 2a, 2b, 8a, and 8b) were more potent than those of THPs. Nitration of the sugar moiety in THPs resulted in a vascular relaxing effect unobserved in the case of THPs.
The fresh rhizomes of Curcuma xanthorrhiza Roxb. were investigated for terpenoids and curcuminoids. Nine sesquiterpenoids, alpha-curcumene (1), arturmerone (2), xanthorrhizol (3), germacrone (4), beta-curcumene (6), beta-sesquiphellandrene (9), curzerenone (10), alpha-turmerone (11) and beta-turmerone (12), and three curcuminoids, curcumin (7), mono-demethoxycurcumin (8) and bis-demethoxycurcumin (13), were isolated and one monoterpenoid, camphor (5), was identified by capillary GC-MS. Four species of C. xanthorrhiza could be classified into two chemotypes by their bisabolane-type sesquiterpenoid compositions. The first type contained large amounts of 2, 11 and 12 (CX I type). The second type contained large amounts of 1, 3 and 6, and none of 2, 9, 11 and 12 (CX II type). These two chemotypes, CX I type and CX II type, were compared with the two chemotypes of C. longa L., CL I type and CL II type, on their contents by capillary GC and HPLC analysis. It was found that all of them contained curcuminoids, 7, 8 and 13 and large amounts of various bisabolane-type sesquiterpenoids.
Intra- and extracellular sodium in guinea pig erythrocytes was evaluated with sodium-23 nuclear magnetic resonance (23Na-NMR) by the use of a shift reagent, Dy(TTHA)3- or Dy(PPPi)2(7-). The test medium contained erythrocytes at 40% hematocrit level and NMR buffer (145 mM NaCl, 10 mM Dy(TTHA)3-, 10% D2O, adjusted to pH 7.4 with tris, at 35 degrees C). NMR spectra were obtained with a JEOL GSX 400 spectrometer operating at the Fourier transform mode of resonance signals, and the accumulated signals provoked by radio-frequency pulses of 90 degrees were recorded on paper. Quantitative Na determination was performed by measuring the area under the peak of intracellular sodium (Nai) NMR signals. Ouabain (Oua: 0.3 mM) and asebotoxin-III (ATX-III: 0.3 mM) produced an increase in Nai-NMR signals to a level of 188.1% and 138.1% of the control, respectively. Combined use of Oua (0.15 mM) and ATX-III (0.15 mM) produced an elevation of Nai concentration to a high level of 219.0% of the control in a superadditive manner. Mechanisms of the Nai elevation with Oua and ATX-III can be interpreted by assuming two different actions: ATX-III increases net Na(+)-influx via Na+ channels, while Oua inhibits the pumping out of Na+ from the cell.
Plumbagin, an active principle from Plumbaginaceous plants, produced a triphasic inotropic response (first positive, second negative, and third positive phases) in guinea-pig papillary muscle. The inotropic potency of plumbagin at the first positive phase was pD2 6.40, and the methylation of 5-hydroxy group of plumbagin reduced the potency. The triphasic pattern of inotropism of plumbagin was unaffected by reserpine or propranolol treatments. Plumbagin did not produce the positive inotropic effects under anoxic conditions or in the presence of mitochondrial oxidative phosphorylation inhibitors such as 2,4-dinitrophenol and dicumarol.
Taspine has been isolated as a cytotoxic substance from Sangre de Grado, sap of Croton palanostigma (Euphorbiaceae), by bioassay guided fractionation. The cytotoxicity (IC50) of taspine was found to be 0.39 microgram/ml against KB cells and 0.17 microgram/ml against V-79 cells.
The Diels-Alder reactions of a cardiac glycoside, proscillaridin (1), with some dienophiles were investigated. The reaction of 1 with alkenes such as methyl vinyl ketone and methyl acrylate afforded 3-oxo-2-oxabicyclo[2.2.2]oct-7-enes (2-5) and para-substituted benzene derivatives (6 and 7), while 1 reacted with alkynes (3-butyn-2-one, methyl propiolate) to yield para- or meta-substituted benzene derivatives (6-9). The biological activities of the resulting derivatives were evaluated by the use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase (ATPase) preparation from dog kidney. Among the proscillaridin derivatives, compounds 4 and 7 moderately inhibited Na+,K(+)-ATPase activity. Furthermore, the concentration range of 7 over which its positive inotropic effect on guinea-pig papillary muscle preparations, increased from 5% to 95% of maximum was broader than that of 1, i.e., concentration dependency was maintained over a greater range of concentration.
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Casearins G-R, new cytotoxic clerodane diterpenes have been isolated from the leaves of Casearia sylvestris Sw. (Flacourtiaceae). Their structures have been elucidated by spectroscopic methods and chemical conversions, and their structure-activity relationships have been discussed.
To reduce the vascular contracting effect of the cardiac glycoside, proscillaridin (1), all kinds of its nitrates were prepared by utilizing effectively an isopropylidene function as a protective group. The pharmacological activities of proscillaridin nitrates were evaluated by the use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase preparations from the dog kidney. Furthermore, the effect for smooth muscle using the helical strips isolated from 13-week old spontaneously hypertensive rat was examined. The positive inotropic effects and Na+, K(+)-adenosine triphosphatase inhibition activities of mononitrates (6, 9, 15) and dinitrates (3, 4, 5) were a little less potent than 1, but those of trinitrate (2) were much reduced. Every nitrate did not exhibited a vascular contracting effect but a relaxing effect. Among them, the vascular relaxing effects of 2',3'-dinitrate (3) and 2',4'-dinitrate (4) were more potent than those of the other nitrates.
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Bacterial growth and lethality of Listeria monocytogenes in mice were augmented by carrageenan-treatment and X-irradiation (8 J kg-1), whereas growth and lethality of Pseudomonas aeruginosa were augmented by X-irradiation but not by carrageenan-treatment. Protection against L. monocytogenes, at least in the early phases, appears to depend mainly on macrophages, since carrageenan depletes macrophages but not polymorphonuclear cells (PMN), whereas protection against P. aeruginosa appears to depend mainly on PMN. Ineffectiveness of PMN in elimination of L. monocytogenes is supported by histological examination and observation of intracellular killing in vitro.