title: N-phosphonocarbonylpyrrolidine derivatives of guanine: a new class of bi-substrate inhibitors of human purine nucleoside phosphorylase.
abstract: A complete series of pyrrolidine nucleotides, (3R)- and (3S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acids and (3S,4R)-, (3R,4S)-, (3S,4S)-, and (3R,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acids, were synthesized and evaluated as potential inhibitors of purine nucleoside phosphorylase (PNP) isolated from peripheral blood mononuclear cells (PBMCs) and cell lines of myeloid and lymphoid origin. Two compounds, (S)-3-(guanin-9-yl)pyrrolidin-1-N-ylcarbonylphosphonic acid (2a) and (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid (6a), were recognized as nanomolar competitive inhibitors of PNP isolated from cell lines with K(i) values within the ranges of 16-100 and 10-24 nM, respectively. The low (MESG)K(i) and (Pi)K(i) values of both compounds for PNP isolated from PBMCs suggest that these compounds could be bisubstrate inhibitors that occupy both the phosphate and nucleoside binding sites of the enzyme.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nám. 2, 166 10 Prague 6, Czech Republic. rejman@uochb.cas.cz
authors.forename: Dominik
authors.initials: D
authors.lastname: Rejman
authors.forename: Natalya
authors.initials: N
authors.lastname: Panova
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.forename: Bokang
authors.initials: B
authors.lastname: Maswabi
authors.forename: Radek
authors.initials: R
authors.lastname: Pohl
authors.forename: Ivan
authors.initials: I
authors.lastname: Rosenberg
mesh_terms: D045744:Cell Line, Tumor; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D006150:Guanine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D010757:Phosphorous Acids; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C572351:3-(guanin-9-yl)pyrrolidin-N-ylcarbonylphosphonic acid; C572352:4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid; D006150:Guanine Nucleotides; D063065:Organophosphonates; D010757:Phosphorous Acids; D011759:Pyrrolidines; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase