Biomedical subjects
Publications and source records attributed to K Takeya.
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.
New antitumor clerodane diterpenes, named casearins A-F, have been isolated from the leaves of Casearia sylvestris Sw. (Flacourtiaceae). These structures have been completely elucidated by two dimensional nuclear magnetic resonance, circular dichroism spectroscopy, X-ray analysis, and chemical evidences.
Murrayaquinone-A, a carbazole alkaloid, was found to produce a triphasic inotropic response (first positive, second negative and third positive phases) of guinea-pig papillary muscle that normally paced at a slow rate of 0.2 Hz in Krebs-Henseleit solution at 30 degrees C. Murrayaquinone-A produced a concentration-dependent (10(-6) M-10(-4) M) positive inotropic effect (pD2 value 5.27 evaluated at the first phase). The triphasic pattern of inotropism of murrayaquinone-A was unaffected by reserpine, metoprolol or cimetidine treatment. Murrayaquinone-A increased the initial upstroke and the duration of the slow action potential in partially depolarized muscle (external K+ = 30 mEq). Murrayaquinone-A did not cause any positive inotropy under anoxic conditions and in the presence of 2,4-dinitrophenol and dicumarol. These results indicated that the triphasic inotropic effect of murrayaquinone-A is not mediated through a receptor mechanism but through a novel mechanism involving mitochondrial ATP production, thereby increasing the slow inward calcium current across the cardiac cell membrane via cyclic AMP converted from mitochondrial ATP.
The extract of seeds of Euphorbia lathyris L. showed antitumor activity against Sarcoma 180 ascites in mice. Systematic fractionation of the extract led to the characterization of ingenol-3-hexadecanoate as an active principle, together with an inactive diterpene ingenol-20-hexadecanoate.
The effects of structure around the 3- and 5-alkoxycarbonyl groups and the 2-carbamate groups of 4-(2,3-dichlorophenyl)-2-carbamoyloxymethyl dihydropyridine derivatives were investigated, concerning their vasodilating action, plasma level, hypotensive action and acute toxicity. High negative linear correlation was found between the plasma levels and the number of C atoms in esterifying alkyl groups in 3- and 5-positions of the dihydropyridine ring. High plasma levels and effective hypotensive action were found in compounds having lower alkyls as esterifying groups of 3- and 5-carboxyl groups, among 2-unsubstituted derivatives.
The chemical constituents of Japanese mistletoes, Taxillus yadoriki Danser, Taxillus kaempferi Danser, and Korthalsella japonica Engler, epiphyting to different host trees were compared, and the antimicrobial and hypotensive properties of some isolated flavonoids were examined. Two known flavonoid glycosides, hyperin and quercitrin, were isolated from Taxillus yadoriki Danser, together with fatty acids, phytosterol, and phytosterol-glucoside. There was remarkable variation of contents of quercitrin among the plants on different host trees. From Taxillus kaempferi Danser, fatty acids, phytosterol, phytosterol-glucoside, quercetin, avicularin, and taxillusin were isolated, and quercitrin and hyperin were also identified. There was no remarkable variation of compositions of flavonoid glycosides among the plants on different host trees. A known flavone glycoside, chrysoeriol-4'-O-glucoside, was isolated from Korthalsella japonica Engler, together with fatty acids, phytosterol, oleanolic acid, and phytosterol-glucoside. Chrysoeriol-4'-O-glucoside is contained in this plant irrespective of the host trees.
With the aim of obtaining compounds with strong antitumor activity, a quantitative structure-activity relationship (QSAR) of antitumor phenolic compounds (long-chain phenols) was derived using the Hansch-Fujita equation. The ED50 values against Chinese hamster V-79 cells were analyzed in terms of log P as the hydrophobic parameter and the energy of the lowest unoccupied molecular orbital (ELUMO) calculated by using the modified neglect of differential overlap (MNDO) method as the electronic parameter, by means of multiple regression analysis. It was found that the activities mainly depended on log P (an optimum log P of 8.3) and a low-lying ELUMO value. 4-Undecylcatechol, selected on the basis of the above results, exhibited strong antitumor activity against Sarcoma 180 ascites and P-388 lymphocytic leukemia.
A technique to assay Na+ ions in cells is presented. Intracellular and extracellular Na+ ions in a suspension of guinea pig erythrocytes were conveniently determined by using sodium-23 nuclear magnetic resonance (23Na-NMR), in combination with two anionic shift reagents: Dy(TTHA)3- and Dy(PPPi)2(7-). Monensin (1), monensylalanine (2b), monensylserine (2c), and monensylphenylalanine (2d) induced large increases of intracellular Na+ ion concentration ([Nain]), while monensylglycine (2a), monensyltyrosine (2e), monensylaspartic acid (2f), and monensylglutamic acid (2g) showed slight increases. The values of initial increasing rate (Vi) of 2a-g were much smaller than that of 1. This fact was probably due to the lower lipophilicity of 2a-g than 1, because a good correlation was observed between Vi and Rm50 values of 1 and 2a-g. This lower lipophilicity is a consequence of conformational differences between 1 and 2a-g.
The pharmacological actions such as analgesic effect, diuretic action, hypoglycemic activity and hypotensive action were studied on the methanol extract of the Japanese mistletoe and the European mistletoe. The both extracts showed the hypotensive action when administered intravenously to cat. The methanol extract of the Japanese mistletoe also showed a increase of K+ value in the urine when administered orally to rat.
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