2001 Fiscal Year Final Research Report Summary
Studies of Phenazine di N-Oxides as a New Type of Hydroxy Radical Donor
| Project/Area Number |
12672169
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
FUKUHARA Kiyoshi National Institute of Health Sciences, Division of Organic Chemistry, Section Chief, 有機化学部, 室長 (70189968)
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| Co-Investigator(Kenkyū-buntansha) |
MIYATA Naoki National Institute of Health Sciences, Division of Organic Chemistry, Head, 有機化学部, 部長 (50114674)
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| Project Period (FY) |
2000 – 2001
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| Keywords | phenazine / N-oxide / hydroxyl radical / cancer / DNA damage |
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| Research Abstract |
The search for more effective anticancer agents has focus to the development of drugs capable of killing hypoxic tumors, which are considered to pose a problem for both chemotherapy and radiotherapy of cancer. A number of heterocyclic di-N-oxides have been reported to exhibit cytotoxity toward mammarian and bacterial cells. The mechenism of toxicity has been suggested to involve one-electron-reductive activation of the parent N-oxides, which could result in the production of OH and O2-. While the locus of action of these agents has not been established, it seemed reasonable to anticipate that a heterocyclic di-N-oxide capable of binding to DNA and producing diffusible oxygen radicals would effect DNA strand scission. Accordingly, 2aminoalkylphenazine 5, lO-di-N-oxide(1) was designed to produce diffusible oxygen radicals and concomitant DNA strand scission under physiological conditions. In the presence ofNADH, phenazine di-Noxide 1 cleaved DNA in both aerobic and anaerobic conditions. Under anaerobic conditions, the DNA cleaving activities of 1 were quenched with increasing DMSO concentrations, suggesting the generation of hydroxyl radical by taking advantage of oxygen in N-oxide. In order to improve the DNA cleaving ability of phenazine di-N-oxide 1, 2-aminoalkyl-1, 5-dihydroxylphenazine di-N-oxide (2) was also designed and synthesized. The hydrogen binding of hydroxyl substituent with N-oxide might increase the electrophilic nature of 2, resulting the generation of hydroxyl radical with greater facility than 1.In fact, the strong DNAcleaving activity was shown by 2 under anaerobic condition.
Finally, the efficient DNA cleaving activity under anaerobic conditions might enable hydroxylphenazine di-N-oxide 2 to be candidate for antitumor agents capable for killing the hypoxic cells, which are known to be present in many human tumors as target cells.
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Research Products
(16 results)
