title: Nucleoside-(5'→P) methylenebisphosphonodithioate analogues: synthesis and chemical properties.
abstract: Nucleoside-(5'→P) methylenebisphosphonodithioate analogues are bioisosteres of natural nucleotides. The potential therapeutic applications of these analogues are limited by their relative instability. With a view toward improving their chemical and metabolic stability as well as their affinity toward zinc ions, we developed a novel nucleotide scaffold, nucleoside-5'-tetrathiobisphosphonate. We synthesized P1-(uridine/adenosine-5')-methylenebisphosphonodithioate, 2 and 3, and P1,P2-di(uridine/adenosine-5')-methylenebisphosphonodithioate, 4 and 5. Using (1)H and (31)P NMR-monitored Zn(2+)/Mg(2+) titrations, we found that 5 coordinated Zn(2+) by both N7 nitrogen atoms and both dithiophosphonate moieties, whereas 3 coordinated Zn(2+) by an N7 nitrogen atom and Pβ. Both 3 and 5 did not coordinate Mg(2+) ions. (31)P NMR-monitored kinetic studies showed that 3 was more stable at pD 1.5 than 5, with t(1/2) of 44 versus 9 h, respectively, and at pD 11 both showed no degradation for at least 2 weeks. However, 5 was more stable than 3 under an air-oxidizing atmosphere, with t1/2 of at least 3 days versus 14 h, respectively. Analogues 3 and 5 were highly stable to NPP1,3 and NTPDase1,2,3,8 hydrolysis (0-7%). However, they were found to be poor ectonucleotidase inhibitors. Although 3 and 5 did not prove to be effective inhibitors of zinc-containing NPP1/3, which is involved in the pathology of osteoarthritis and diabetes, they may be promising zinc chelators for the treatment of other health disorders involving an excess of zinc ions.
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Meltzer
authors.forename: Yael
authors.initials: Y
authors.lastname: Nadel
authors.forename: Joanna
authors.initials: J
authors.lastname: Lecka
authors.forename: Aviran
authors.initials: A
authors.lastname: Amir
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer
mesh_terms: D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry*; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D004164:Diphosphonates; D009705:Nucleosides; D009946:Organothiophosphorus Compounds; D000249:Adenosine Monophosphate; D014542:Uridine Monophosphate