| 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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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥12,360,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥960,000)
Fiscal Year 2007: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2006: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2005: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | antioxidant / catechin / flavonoid / polyphenol / reactive oxygen species / oxidatiye stress / chemoorevention / アポトーシス |
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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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