Synthesis and biological evaluation of 9-(5′,5′-difluoro- 5′-phosphonopentyl)guanine derivatives for PNP-inhibitors

Sadao Hikishima; MacHiko Isobe; Satoru Koyanagi; Shinji Soeda; Hiroshi Shimeno; Shiroshi Shibuya; Tsutomu Yokomatsu

doi:10.1016/j.bmc.2005.10.017

Synthesis and biological evaluation of 9-(5′,5′-difluoro- 5′-phosphonopentyl)guanine derivatives for PNP-inhibitors

Sadao Hikishima, MacHiko Isobe, Satoru Koyanagi, Shinji Soeda, Hiroshi Shimeno, Shiroshi Shibuya, Tsutomu Yokomatsu

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

Abstract

9-(5′,5′-Difluoro-5′-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of α-methyl and β-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (±)-4.

Original language	English
Pages (from-to)	1660-1670
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	14
Issue number	5
DOIs	https://doi.org/10.1016/j.bmc.2005.10.017
Publication status	Published - Mar 1 2006
Externally published	Yes

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2005.10.017

Cite this

@article{13c09163248a4f1ea96ba9536e46a4ad,

title = "Synthesis and biological evaluation of 9-(5′,5′-difluoro- 5′-phosphonopentyl)guanine derivatives for PNP-inhibitors",

abstract = "9-(5′,5′-Difluoro-5′-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of α-methyl and β-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (±)-4.",

author = "Sadao Hikishima and MacHiko Isobe and Satoru Koyanagi and Shinji Soeda and Hiroshi Shimeno and Shiroshi Shibuya and Tsutomu Yokomatsu",

note = "Funding Information: This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.",

year = "2006",

month = mar,

day = "1",

doi = "10.1016/j.bmc.2005.10.017",

language = "English",

volume = "14",

pages = "1660--1670",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "5",

}

TY - JOUR

T1 - Synthesis and biological evaluation of 9-(5′,5′-difluoro- 5′-phosphonopentyl)guanine derivatives for PNP-inhibitors

AU - Hikishima, Sadao

AU - Isobe, MacHiko

AU - Koyanagi, Satoru

AU - Soeda, Shinji

AU - Shimeno, Hiroshi

AU - Shibuya, Shiroshi

AU - Yokomatsu, Tsutomu

N1 - Funding Information: This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

PY - 2006/3/1

Y1 - 2006/3/1

N2 - 9-(5′,5′-Difluoro-5′-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of α-methyl and β-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (±)-4.

AB - 9-(5′,5′-Difluoro-5′-phosphonopentyl)guanine (DFPP-G) and its hypoxanthine analogue (DFPP-H) were modified by introducing a methyl group to all possible positions of the linker connecting a purine and difluoromethylenephosphonic acid moiety to evaluate the effects of the methyl group on inhibition against purine nucleoside phosphorylase. The methyl group on the linker affected the inhibition in a positional-dependent manner. Inhibitory potency of α-methyl and β-methyl-substituted analogues of DFPP-H increased by about 600- to 1000-fold upon converting to cyclopropane nucleotide analogue (±)-4.

UR - http://www.scopus.com/inward/record.url?scp=31044452914&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=31044452914&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2005.10.017

DO - 10.1016/j.bmc.2005.10.017

M3 - Article

C2 - 16263289

AN - SCOPUS:31044452914

SN - 0968-0896

VL - 14

SP - 1660

EP - 1670

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 5

ER -

Synthesis and biological evaluation of 9-(5′,5′-difluoro- 5′-phosphonopentyl)guanine derivatives for PNP-inhibitors

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this