2004 Fiscal Year Final Research Report Summary
Construction of focused library and the development of protein tyrosine phosphatase inhibitor
| Project/Area Number |
15310144
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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 |
Living organism molecular science
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
SODEOKA Mikiko TOHOKU UNIVERSITY, INSTITUTE OF MULTIDISCIPLINARY RESEARCH FOR ADVANCED MATERIALS, ASSOCIATE PROFESSOR, 多元物質科学研究所, 教授 (60192142)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAI Go RIKEN, Research Scientist, 理化学研究所, 研究員 (50359551)
HAMASHIMA Yoshitaka TOHOKU UNIVERSITY, INSTITUTE OF MULTIDISCIPLINARY RESEARCH FOR ADVANCED MATERIALS, Research Associate, 多元物質科学研究所, 助手 (40333900)
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| Project Period (FY) |
2003 – 2004
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| Keywords | focused library / protein tyrosine phosphatase / inhibitor / tetronic acid / RK-682 / Ascorbic acid / heparanase / protein kinase C |
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| Research Abstract |
Aiming at developing PTP (protein tyrosine phosphatase), a "focused-library" (compounds having a "core" structure that can interact with the conserved catalytic site of PTP as a phosphate mimic and having "various" substituents that may interact with the unique region of each enzyme) was synthesized. Construction of a new library having L-ascorbic acid as a "core" structure was examined. We have already developed an efficient method for carbamate synthesis using a polymer-supported N-hydroxysuccinimide (NHS). Using this method an ascorbic acid-carbamate library was synthesized. The carbamate derivatives were prepared either from 6-amino-ascorbic acid and various alcohols, or from 5-dehydroxy-ascorbic acid and various amines. The inhibitory activity of these compounds (about 80 compounds) toward PTP1B (PTP) was tested, and several compounds showed the moderate inhibitory activity.
The 4-O-alkyated tetronic acid derivatives as second generation library was synthesized, and 4-benzyl-RK-682 has been found to possess a selective inhibitory activity for heparanase. 4-Benzyl-RK-682 also inhibited the invasion and migration of human fibrosarcoma HT 1060 cells.
The isobenzofuranone library was also synthesized, and among them we have found the strong PKCα activators.
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