Structural-based design and synthesis of novel 9-deazaguanine derivatives having a phosphate mimic as multi-substrate analogue inhibitors for mammalian PNPs.
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.
Hikishima
Sadao
S
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Hashimoto
Mariko
M
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Magnowska
Lucyna
L
Department of Biophysics, Institute of Experimental Physics, Warsaw University, Zwirki i Wigury 93, 02 089 Warsaw, Poland.
Bzowska
Agnieszka
A
Department of Biophysics, Institute of Experimental Physics, Warsaw University, Zwirki i Wigury 93, 02 089 Warsaw, Poland.
Yokomatsu
Tsutomu
T
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013154:Spleen / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
C528379:9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase