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

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 P_β. 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 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 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.