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, <b>2</b> and <b>3</b>, and P1,P2-di­(uridine/adenosine-5′)-methylenebisphosphonodithioate, <b>4</b> and <b>5</b>. Using ¹H and ³¹P NMR-monitored Zn²⁺/Mg²⁺ titrations, we found that <b>5</b> coordinated Zn²⁺ by both N7 nitrogen atoms and both dithiophosphonate moieties, whereas <b>3</b> coordinated Zn²⁺ by an N7 nitrogen atom and P_β. Both <b>3</b> and <b>5</b> did not coordinate Mg²⁺ ions. ³¹P NMR-monitored kinetic studies showed that <b>3</b> was more stable at pD 1.5 than <b>5</b>, with <i>t</i>_1/2 of 44 versus 9 h, respectively, and at pD 11 both showed no degradation for at least 2 weeks. However, <b>5</b> was more stable than <b>3</b> under an air-oxidizing atmosphere, with t_1/2 of at least 3 days versus 14 h, respectively. Analogues <b>3</b> and <b>5</b> were highly stable to NPP1,3 and NTPDase1,2,3,8 hydrolysis (0–7%). However, they were found to be poor ectonucleotidase inhibitors. Although <b>3</b> and <b>5</b> 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.