1997 Fiscal Year Final Research Report Summary
Synthesis and SQAR of DNA-Cleaving Propargylic Sulfones
| Project/Area Number |
08044141
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
工業物理化学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
NISHIMOTO Sei-ichi KYOTO UNIVERSITY Graduate School of Engineering, Professor, 工学研究科, 教授 (10115909)
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| Co-Investigator(Kenkyū-buntansha) |
DAI Wei-Min Hong Kong Univ.Science & Technology, Chemistry, Associate Professor, 化学科, 助教授
ZHOU Ling KYOTO UNIVERSITY Graduate School of Engineering, Assistant, 工学研究科, 助手 (50293890)
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| Project Period (FY) |
1996 – 1997
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| Keywords | DNA Cleavage / Propargylic Sulfones / Anti-tumor Compounds / Prodrug / Intercalation / Molecular Recognization / Cytotoxicity / Structure-Activity Relationship |
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| Research Abstract |
New class of propargylic sulfones, that are activated to possess alkylating reactivity toward a specific DNA-base sequence and thereby result in DNA-strand breaks, were designed and synthesized. The following results were obtained through the joint research for 2 years.
(1) The head investigator or the investigator of Kyoto University visited the Hong Kong University of Science and Technology, 2 times in 1996 and 3 times in 1997, investigating the molecular design and synthesis of propargylic sulfone compounds, and the structure-reactivity relationship of DNA-cleaving compounds including natural products.
(2) The investigator of the Hong Kong University of Science and Technology was invited once every year to investigate the research trends on the mechanism by which propargylic sulfones are activated to possess anti-tumor activity and cytotoxicity.
(3) 45 kinds of cis-enediyne type propargylic sulfones, mono-propargylic sulfones and bis-propargylic sulfones were synthesized to quantify th
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e structure-activity relationship on DNA cleavage and cytotoxicity. 1,5-Diyne compounds were identified to generate cis-enediyne structure by rearrangement of an allylic double bond.
(4) For a series of propargylic sulfone compounds, the DNA-cleaving activity was correlated to the intercalating ability to DNA double strand, indicating a trend that mono-propargylic sulfones cause DNA double-strand breaks more readily than bis-analogs. While napthalene and anthracene moieties are efficient function for DNA intercalation, effective DNA cleavage can not be achieved unless the active allenic sulfone moiety is located at the right sites for DNA base alkylation.
(5) A model reaction of propargylic sulfone with guanosine in aqueous solution demonstrated that the active allenic slufone moiety formed in situ alkylates the N7 position of guanosine, followed by hydrolytic release of ribose to give an adduct with guanine. This reaction pathway accounts for the DNA-cleaving activity of propargylic sulfones. Less
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Research Products
(10 results)
