2011 Fiscal Year Final Research Report
Development of biologically active compounds based on features of phosphonyl and phosphinyl functional groups
| Project/Area Number |
21590126
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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 |
Drug development chemistry
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
ANGIESKA Bzowska ワルシャワ大学, 理学部, 教授
HIKISHIMA Sadao 東京薬科大学, 薬学部, 助教 (70398816)
YAMAGISHI Takehiro 東京薬科大学, 薬学部, 講師 (90297606)
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| Project Period (FY) |
2009 – 2011
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| Keywords | ヌクレオチドアナログ / ジフルオロホスホン酸 / PNP阻害剤 / fragment-based drug design / ペプチドイソスター / 遷移状態アナログ |
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| Research Abstract |
9-(5', 5'-Difluoro-5'-phosphonopentyl)-9-deazaguanine(DFPP-DG) was designed as a multi-substrate analogue inhibitor against purine nucleoside phosphorylase(PNP) on the basis of X-ray crystallographic data obtained for a binary complex of 9-(5', 5'-difluoro-5'-phosphonopentyl) guanine(DFPP-G) with calf-spleen PNP. DFPP-DG and its analogous compounds were adjusted by length of the linker achieved by the Sonogashira coupling reaction between a 9-deaza-9-iodoguanine derivative andω-alkynyldifluoromethylene phosphonates as a key reaction. DFPP-DG is a very potent PNP inhibitor with apparent inhibition constants(in the presence of 1 mM phosphate) of 4.4 nM and 8.1 nM vs calf spleen and human erythrocyte PNPs, respectively. One of its analogues, homo-DFPP-DG, with longer chain linking phosphonate and 9-deazaguanine is even more potent vs human enzyme, with an apparent inhibition constant of 5.3 nM(in the presence of 1 mM phosphate). The inhibition constant at equilibrium(1 mM phosphate concentration) with calf spleen PNP was shown to be K_<eqi>=85±13pM(pH7.0, 25℃).
In the research for developing phosphinyl dipeptide isostere(PDIs), we have found a new method for synthesis of optically active PDIs by using chemo-enzymatic processes. We also developed an efficient stereoselective synthesis of the Leu. Pro type PDI. In addition, we have also developed several new methods for synthesis of some new molecules having phosphonyl or phosphiniyl functional group.
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Research Products
(14 results)
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[Journal Article] 1.45A resolution crystal structure of recombinat PNP in complex with a pM multisubstrate analogue inhibitor bearing one feature of posutulated transition state2010
Author(s)
G. Chojnowski, K. Breer, M. Narczyk, B. Wielgus-Kutrowska, H. Czapinska, M. Hashimoto, S. Hikishima, T. Yokomatsu, M. Bochtler, A. Girstun, K. Staro., A. Bzowska
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Journal Title
Biochem. Biophys. Res. Comm
Volume: 391
Pages: 703-708
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[Presentation]2010
Author(s)
T. Haruki, H. Ichikawa, J. Mori, T. Yamagishi, T. Yokomatsu
Organizer
18^<th> International Conference on Phosphorus Chemistry
Place of Presentation
Wroclaw, Poland
Year and Date
20100700
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