Development of zinc chelators with protein specificity aiming at molecular target therapy of cancer
| Project/Area Number |
17390030
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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 | Kumamoto University |
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Principal Investigator |
OTSUKA Masami Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Professor (40126008)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMAOTO Yoshinari Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Assistant Professor (20194409)
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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 |
¥15,810,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2007: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2006: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2005: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | cancer / zinc protein / chelator / molecular target |
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| Research Abstract |
The present research aims at the development of inhibitors of zinc proteins designed by combing a zinc chelator and a protein recognition moiety. We were interested farnesyltransferase and ADAM family protease as zinc proteins to be inhibited.
Synthetic study of farnesyltransferase inhibitors
A zinc protein farnesyltransferase catalyzes the farnesylation of an oncogene product Ras to induce the oncogenic function of Ras. The objective of the present study is to obtain inhibitors by introducing a farnesyl phosphate, a farnesyltransferase-recognition moiety, into a zinc chelator comprising a pyridine and cysteamine side chains.
Considering the instability of the farnesyl group, a 4-aminopyridine chelator was first synthesized. The farnesyl moiety was then successfully introduced by the formation of phosphoramide linkage between the 4-amino group and farnesyl phosphate.
Synthetic study of ADAM family protease inhibitors
Adhesive molecule CD44 is known to be closely related to proliferation, invasion and metastasis of cancer cells. The cell adhesion and the cell movement are due to the cleavage of the extracellular domain of the CD44 by ADAM family proteases, resulting the cancer metastasis and invasion.
The present study employed marimastat, an ADAM 30 inhibitor, as the ADAM family protease recognition moiety. Thus (D)-Tartrate was converted into the corresponding eposide and an isobutyl group was introduced to obtain a key intermediate, a marimastat precursor. The coupling of the marimastat moiety thus obtained and the zinc chelator was attempted.
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Report
(4 results)
Research Products
(24 results)
