Nucleoside-(5′→P) methylenebisphosphonodithioate analogues: Synthesis and chemical properties

Diana Meltzer, Yael Nadel, Joanna Lecka, Aviran Amir, Jean Sévigny, Bilha Fischer

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4 Scopus citations


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 1H and 31P NMR-monitored Zn2+/Mg2+ titrations, we found that 5 coordinated Zn2+ by both N7 nitrogen atoms and both dithiophosphonate moieties, whereas 3 coordinated Zn2+ by an N7 nitrogen atom and Pβ. Both 3 and 5 did not coordinate Mg 2+ ions. 31P NMR-monitored kinetic studies showed that 3 was more stable at pD 1.5 than 5, with t1/2 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 t 1/2 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.

Original languageEnglish
Pages (from-to)8320-8329
Number of pages10
JournalJournal of Organic Chemistry
Issue number17
StatePublished - 6 Sep 2013


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