Mutsuo Kozuka

Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.

Anti-tumor promoting activity of polyphenols from Cowania mexicana and Coleogyne ramosissima

Chemical investigation on polyphenol-rich fractions of Cowania mexicana and Coleogyne ramosissima (Rosaceae) which showed significant inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), has led to the characterization of 10 compounds including C-glucosidic ellagitannin monomers and dimers from the former plant, and 17 polyphenols including flavonoid glycosides from the latter. The effects of individual components and their analogues with related structures on the TPA-induced EBV-EA activation were then evaluated. Among the compounds isolated from C. mexicana, two C-glucosidic ellagitannins, alienanin B and stenophyllanin A and a nitrile glucoside (lithospermoside), and among the constituents from C. ramosissima, two flavonoid glycosides, isorhamnetin 3-0-beta-D-glucoside and narcissin were revealed to possess strong inhibitory effects on EVB-EA activation, the potencies of which were either comparable to or stronger than that of a green tea polyphenol, (-)-epigallocatechin gallate. These polyphenols except for nitrile glucoside, which was not tested owing to an insufficient amount, were also found to exhibit anti-tumor promoting activity in two-stage mouse skin carcinogenesis using 7,12-dimethylbenz[a]anthracene (DMBA) and TPA.

Antitumor-promoting effects of cyclic diarylheptanoids on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis

Eleven cyclic diarylheptanoids were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. 13-Oxomyricanol and myricanone showed the highest activity and also exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that certain diarylheptanoids might be valuable antitumor promoters and/or chemopreventors.

Chemopreventive potential of cyclic diarylheptanoids

Eleven cyclic diarylheptanoids and seven related compounds were screened as potential antitumor promoters by using the in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) activation assay. In addition, the cyclic diarylheptanoid myricanone (2) was examined for antitumor initiating activity in a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite as an initiator and TPA as a promoter. Myricanone (2) exhibited significant antitumor-initiating effect on mouse skin. These data suggest that cyclic, as well as linear, diarylheptanoids might be valuable chemopreventors.

Cancer preventive agents. Part 8: Chemopreventive effects of stevioside and related compounds

In a search for potential cancer chemopreventive agents from natural resources, stevioside (1), a sweetener, and six related compounds, including two aglycones steviol (6) and isosteviol (7), were screened in an in vitro assay for inhibitory effects on Epstein-Barr virus early antigen activation. Compounds 1, 6 and 7 showed significant activity in this assay and also exhibited strong inhibitory effects in a two-stage carcinogenesis test using mouse skin induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effects of these three compounds were greater than that of glycyrrhizin. Furthermore, these three compounds significantly inhibited mouse skin carcinogenesis initiated by peroxynitrite and promoted by TPA. Their activities were comparable to that of curcumin. These results suggested that 1, as well as 6 and 7, could be valuable as chemopreventive agents for chemical carcinogenesis.

Inhibitory effects of 12-O-tetradecanoylphorbol-13-acetate and teleocidin B induced epstein-barr virus by saponin and its related compounds

The inhibitory effects of triterpene glycosides and monoterpene glycosides on 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin B in the Epstein-Barr virus (EBV) activation in Raji cells were studied. Concomitant treatment of Raji cells with TPA or Teleocidin B and these glycosides showed the inhibition of EBV activation. We herein report in vitro structure-activity studies using a biological test system on a variety of triterpene glycosides having 1 sugar chain (monodesmoside), 2 sugar chain (bisdesmoside) and an acyl side-chain. Among these glycosides, triterpene 3-O-glycosides and acylated saponin exhibited an effective inhibition of EBV activation; therefore, the sugar chain at C-3 of the triterpene and/or the acyl side-chain were determined to be essential to the inhibitory activities in this test system. The data suggested that these triterpenoid glycosides which were originally used as herbal drugs and folk remedies in many areas of the world, were in fact inhibitory compounds, thus explaining the EBV activation in the in vitro test system.

Flavonoid and benzophenone glycosides from Coleogyne ramosissima.

A benzophenone glucoside and two flavonol glycosides were isolated together with 27 known polyphenols from the aerial parts of Coleogyne ramosissima, and their structures were elucidated by spectroscopic and chemical methods as iriflophenone 2-O-beta-glucopyranoside, isorhamnetin 3-O-2G-rhamnopyranosylrutinoside-7-O-alpha-rhamnopyranoside and limocitrin 3-O-rutinoside-7-O-beta-glucopyranoside, respectively.

Cancer Preventive Agents. Part 5. Anti-tumor-Promoting Effects of Coumarins and Related Compounds on Epstein-Barr Virus Activation and Two-stage Mouse Skin Carcinogenesis

Abstract A series of coumarins and related compounds were synthesized and screened as potential anti-tumor-promoting agents by examining the ability of the compound to inhibit Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O.-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The most promising compound in this in vitro. assay, 7,8-di(3-methyl-2-butenyloxy)coumarin (17), showed confirmed chemopreventive activity in an in vivo. two-stage assay of mouse skin tumors (DMBA/TPA). This investigation also confirmed an important role for the prenyl moiety, and, possibly, for the dimethylpyran substructure, on the anti-tumor-promoting activity.

Antitumor agents 220. Antitumor-promoting effects of cimigenol and related compounds on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis.

Cimigenol (1) and 39 related compounds were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. Structure-activity relationship analysis indicated that compound 1 showed the highest activity and also exhibited significant inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that 1 and the related compounds might be valuable anti-tumor promoters.

Alteration of Na+ permeability in human erythrocytes as studied by 23Na-NMR and inhibition of the kidney Na+,K+-ATPase activities with saponins: Interaction of Gleditsia saponins with human erythrocyte membranes

Abstract Interaction of Gleditsia saponin C 1 , bis-monoterpenyl echinocystic acid 3,28-O-bisglycoside, with human erythrocyte membranes and artificial membranes was investigated by means of the hemolytic activities, alteration of Na + permeability by 23 Na-NMR spectroscopy and inhibition of Na + ,K + -ATPase activities. Interaction of Gleditsia saponin C ( 1 ), bis-monoterpenyl echinocystic acid 3,28-O-bisglycoside, with human erythrocyte membranes and artificial membranes was investigated by means of the hemolytic activities, alteration of Na + permeability by 23 Na-NMR spectroscopy and inhibition of Na + ,K + -ATPase activities.