2005 Fiscal Year Final Research Report Summary
Synthesis of adenine derivatives possessing interferon inducing activity and creation of receptor ligand with high affinity
| Project/Area Number |
16590087
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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 | Gifu Pharmaceutical University |
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Principal Investigator |
HIROTA Kosaku Gifu Pharmaceutical University, professor, 薬学部, 教授 (90082982)
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| Co-Investigator(Kenkyū-buntansha) |
SAJIKI Hironao Gifu Pharmaceutical University, Associate Professor, 薬学部, 助教授 (50275096)
MAEGAWA Tomohiro Gifu Pharmaceutical University, Assistant, 薬学部, 助手 (40363890)
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| Project Period (FY) |
2004 – 2005
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| Keywords | interferon-inducing activity / 8-hydroxyadenine / deazaadenine / tool-like receptor / TRL-7 / affinity ligand / fluorescence ligand |
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| Research Abstract |
Recently, we found that 9-benzyl-8-hydroxyadenine (1)possesses relatively potent interferon (IFN)-inducing activity as a lead compound. Further effort to establish the structure-activity relationship reached 2-butoxy- 9-bennzyl- 8-hydroxyandenine (2)as the most active compounds, whose potencies were 10^4-fold greater than that of the lead compound (1). In this research synthesis of higher active analog and fluorescent ligand for Toll-like receptor 7 (TLR-7), whose agonist is such 8-hydroxyandenies, were investigated and the following results were obtained.
1)Chemical modification of the 2-position of adenines : Introduction of various substituents into the 2-position were attempted. 2-MeO(CH_2)_2O- and 2-MeOCH_2S- analogs indicated similar activity to compound 2.
2)Synthesis of 1- or 3- deazaadenine derivatives : The oral bioavailability of compound 2 is remarkably low. Synthesis of 1- or 3-deaza analogs, which are expected increase of lipophilicity, was planed to improve the oral absorption of compound 2. Synthesis of 9-benzyl-2-butoxy-3-deazaadenine (3) and 9-Benzyl-2-butoxy-1-deazaadenine (4) were establiched using 4-amino-2,6-dichloropyridine as a starting compound. Now introduction of an 8-hydroxy group into the deazaadenines (3 and 4) is carried out.
3)Synthesis of fluorescent ligand for Toll-like receptor 7 (TLR-7) : 8-Hydroxyadenine (2) is a strong agonist of TLR-7 and mutual interaction causes production of a large amount of IFN. Synthesis of 8-hydroxyadenine derivative possessing a fluorescent functional group instead of benzyl group at the 9-position was investigated as a probe for analysis of the structure and function of TLR-7. Introduction of anthranylmethyl group resulted in failure in performance caused by low solubility. Various synthetic approaches are now under investigation.
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