Structural-based design and synthesis of novel 9-deazaguanine derivatives having a phosphate mimic as multi-substrate analogue inhibitors for mammalian PNPs

Sadao Hikishima; Mariko Hashimoto; Lucyna Magnowska; Agnieszka Bzowska; Tsutomu Yokomatsu

doi:10.1016/j.bmc.2010.01.062

Structural-based design and synthesis of novel 9-deazaguanine derivatives having a phosphate mimic as multi-substrate analogue inhibitors for mammalian PNPs

Bioorg Med Chem. 2010 Mar 15;18(6):2275-2284. doi: 10.1016/j.bmc.2010.01.062. Epub 2010 Feb 4.

Authors

Sadao Hikishima¹, Mariko Hashimoto¹, Lucyna Magnowska², Agnieszka Bzowska², Tsutomu Yokomatsu¹

Affiliations

¹ School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
² Department of Biophysics, Institute of Experimental Physics, Warsaw University, Zwirki i Wigury 93, 02 089 Warsaw, Poland.

PMID: 20189401
DOI: 10.1016/j.bmc.2010.01.062

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 synthesized by the Sonogashira coupling reaction between a 9-deaza-9-iodoguanine derivative and omega-alkynyldifluoromethylene phosphonates as a key reaction. The experimental details focused on the synthetic chemistry along with some insights into the physical and biological properties of newly synthesized DFPP-DG derivatives are disclosed.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cattle
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Erythrocytes / enzymology
Guanine / analogs & derivatives*
Guanine / chemical synthesis
Guanine / chemistry
Guanine / pharmacology
Humans
Hydrogen-Ion Concentration
Kinetics
Models, Molecular
Molecular Structure
Organophosphonates / chemical synthesis*
Organophosphonates / chemistry
Organophosphonates / pharmacology*
Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
Purine-Nucleoside Phosphorylase / chemistry
Purine-Nucleoside Phosphorylase / metabolism
Spleen / enzymology
Stereoisomerism
Structure-Activity Relationship
Time Factors

Substances

9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine
Enzyme Inhibitors
Organophosphonates
Guanine
Purine-Nucleoside Phosphorylase