2007 Fiscal Year Final Research Report Summary
Design and Synthesis of Antioxidant for a New Type of Chemopreventive Agents
| Project/Area Number |
17390033
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
KIYUOSHI Fukuhara National Institute of Health Sciences, Division of Organic Chemistry, Section Chief (70189968)
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| Co-Investigator(Kenkyū-buntansha) |
OKUDA Haruhiro National Institute of Health Sciences, Division of Organic Chemistry, Head (30160807)
UMEMURA takashi National Institute of Health Sciences, Division of Pathology, Section Chief (50185071)
SHODA Takuji National Institute of Health Sciences, Division of Organic Chemistry, Researcher (60435708)
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| Project Period (FY) |
2005 – 2007
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| Keywords | antioxidant / catechin / flavonoid / polyphenol / reactive oxygen species / oxidatiye stress / chemoorevention |
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| Research Abstract |
The protective role of antioxidants against free-radical-associated diseases has been widely studied, and this has prompted the development of new types of antioxidants to remove reactive oxygen species, such as O_2- and OH. We synthesized planar catechin analogues (PCx, x=1-9) in which catechol (B ring) and chroman moieties (AC ring) in catechin structure are constrained to be planar. Antioxidative properties and effects on human cancer cell lines were also investigated.
1) Synthesis of PC1 was performed via oxa-Pictet Spengler reaction using native catechin and acetone in the presence of TMSOTf. The spectroscopic and kinetic studies of PC1 demonstrated that the rate of the scavenging reaction of galvinoxyl radical by PC 1 is about 5-fold faster than that by the native catechin. PC 1 showed an enhanced protecting effect against the oxidative DNA damage induced by the Fenton reaction without the pro-oxidant effect, which is usually observed in the case of catechin. We also synthesized lipophilic planar catechin analogues (PC2-PC9) with different lengths of carbon side chains by the reaction of catechin and ketone ([CH3 (CH_2)nl_2CO, n=1-8) instead of aceton. It was found that the larger the number of the carbon in the side chains was, the faster radical-scavenging abilities became.
2) Cancer chemopreventive activity of resveratrol, a major polyphenol present in grape, is attributed to the growth inhibition of tumor cells. Therefore, effect of PC1 in cancer cell lines, HL60 and U937, was investigated to evaluate its cancer chemopreventive activity. PC1 induced marked growth inhibition in both cell lines, with IC_<50> values of 50-100μM, which were comparable to that of resveratrol. In addition, induction of apoptosis was demonstrated by the appearance of DNA fragmentation.
Finally, marked antioxidative ability and growth inhibition of cancer cell lines may provide a possibility for the use of PCx in cancer chemoprevention.
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[Journal Article] Effect of MethyI Substitution on Antioxidative Property and Genotoxicity of Resveratrol2008
Author(s)
K. Fukuhara, I. Nakanishi, A. Matsuoka, T. Matsumura, S. Honda, M. Hayashi, T. Ozawa, N. Miyata, S. Saito, N. Ikota, H. Okuda
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Journal Title
Chem. Res. Toxicol. 21
Pages: 282-287
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Enhanced Radical-Scavenging Activity of Naturally-Oriented Artepillin C Derivatives2008
Author(s)
S. Manda, I. Nakanishi, K. Ohkubo, Y. Uto, T. Kawashima. K. Fukuhara, H. Okuda, H. Hori, T. Ozawa, N. Ikota, S. Fukuzumi, K. Anzai
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Journal Title
Chem. Commun.
Pages: 626-628
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] involvement of Electron Transfer in Radical-Scavenging Reaction of Resveratrol2007
Author(s)
I. Nakanishi, T. Shimada, K. Ohkuboo, T. Shimizu, S. Urano. H. Okuda, N. Miyata, T. Ozawa, K. Anzai, S. Fukuzumi, N. Ikota, K. Fukubara
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Journal Title
Chem. Lett. 36
Pages: 1276-1277
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Planar catechin analogues with alkyl side chains, as a potent antioxidant and an α-glucosidase inhibitor2006
Author(s)
W. Hakamata, I. Nakanishi, Y. Masuda, T. Shimizu, H. Higuchi, Y. Nakamura, T. Oku, S. Saito, S. Urano, T. Ozawa, N. Ikota, N. Miyata, H. Okuda, K. Fukuhara
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Journal Title
J. Am. Chem. Soc. 128
Pages: 6524-6525
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Structural basis for DNA cleaving-activity of resveratorl in the presence of Cu(II)2006
Author(s)
K. Fukuhara, M. Nagakawa, I. Nakanishi, K. Ohkubo, K. Imai, S. Urano. S. Fukuzumi, T. Ozawa, N. Ikota, M. Mochizuki, N. Miyata, H. Okuda
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Journal Title
Bioorg. Med. Chem. 14
Pages: 1437-1443
Description
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[Journal Article] Hydroxyl Radical Generation via Photoreduction of a Simple Pyridine N-Oxide by an NADH Analogue, Org.2005
Author(s)
Nakanishi, C. Nishizawa, K. Ohkubo, K. Takeshita, K. Suzuki, T. Ozawa, S. M. Hecht, M. Tanno, S. Sueyoshi, N. Miyata, H. Okuda, S. Fukuzumi, N. Ikota, K. Fukuhara
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Journal Title
Biomol. Chem 3
Pages: 3263-3265
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Eclectron-Tansfer Mechanism in Radical-Scavenging Reactions by a Vitamin E Model in Protic Medium2005
Author(s)
I. Nakanishi, T. Kawashima, K. Ohkubo, H. Kanazawa, K. Inami, M. Mochizuki, K. Fukubara, H. Okuda, T. Ozawa, S. Itoh, S. Fukuzumi, N. Ikota
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Journal Title
Org. Biomol. Chem 3
Pages: 626-629
Description
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[Presentation] Structure-Activity Relationships in the Radical-scavenging Reaction of Polyphenolic Flavones, Oxgen Club of Californai 2008 World Congress, California2008
Author(s)
I. Kahanishi, K. Ohkubo, K. Miyazaki, S. Urano, H. Okuda, N. Ikota, K. Anzai, S. Fukuzumi, T. Ozawa, K. Fukuhara
Place of Presentation
USA
Year and Date
20080300
Description
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[Presentation] Intramolecular Base-Accelerated Radical-Scavenging Reaction of a Planar Catechin Derivative having a Lysine Moiety, 14th Annual Meeting of the Society for Free Radical Biology and Medicine(Sfrbm), Washington, D. C.2007
Author(s)
K. Fukuhara, I. Nakanishi, M. Obara, K. Ohbubo, T. Kawashima, T. Ozawa, N. Ikota, K. Anzai, S. Fukuzumi, N. Miyata, S. Saito, H. Okuda
Place of Presentation
USA
Year and Date
20071100
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Electron-Transfer Mechanism in the Radical-Scavenging Reaction of Resveratrol, 14th Annual Meeting of the Society for Free Radical Biology and Medicin(SFRBM), Washington, D. C.2007
Author(s)
I. Nakanishi, T. Shimada, K. Ohkubo, S. Manda, S. Urano, H. Okuda, n. Miyata, t. Ozawa K. Anzai, S. Fukuzumi, N. Ikota, K. Fukuhara
Place of Presentation
USA
Year and Date
20071100
Description
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[Presentation] Enhanced radical-scavenging activities of planar catechin derivatives having Lysine Moiety, 128th Annual Meeting of the Phamaceutical Society of Japan2006
Author(s)
K. Fukuhara, I. Nakanishi, K. Okubo, N. Fukai, T. Ozawa, N. Miyata, S. Urano, S. Fukuzami, K. Anzai, H. Okuda
Place of Presentation
Yokohama
Year and Date
20060300
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Involvement of Electron Transfer in the Radical-Scavenging Reaction of Resveratrol128th Annual Meeting of the Pharmaceutical Society of Japan2006
Author(s)
I. Nakanishi, T. Shimada, K. Okubo, S. Manda, T. shimizu, S. Urano, H. Okuda, N. Miyata, T.Ozawa K. Anzai, S. Fukuzami, N. Ikota, K. Fukuhara
Place of Presentation
Yokohama
Year and Date
20060300
Description
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[Presentation] Enhanced radical-scavenging activities of planar catechin derivatives having alkyl side chains2005
Author(s)
K. Fukuhara, I. Nakanishi, T. Kawashima, H. Yakumaru, H. Kanazawa, H. Okuda, K. Ohkubo, T. Ozawa, S. Fukuzumi, N. Ikota
Organizer
Pacifichem 2005
Place of Presentation
Honolulu, Hawaii, USA
Year and Date
20051200
Description
「研究成果報告書概要(欧文)」より
