Synthesis of Enzymatically and Chemically Non-hydrolyzable Analogues of Dinucleoside Triphosphates Ap₃A and Gp₃G

Abstract

Dinucleoside polyphosphates are ubiquitous compounds tightly involved in the regulation of a number of key biological processes. Hydrolysis-resistant analogues of Ap(3)A and Gp(3)G, two important members of that family of nucleotides, have been synthesized. P(1),P(2):P(2),P(3)-Bis-methylene diadenosine and diguanosine triphosphates were prepared from O,O-dialkyl methaneselenophosphonates using an original methodology. Whereas the 2-fold addition of the methanephosphonate anion to the activated phosphorus species cannot be performed, multiple condensation of lithiated methaneselenophosphonate with electrophilic trivalent phosphorus compounds is revealed to be very effective. A one-pot condensation/esterification/oxidation sequence involving O,O-dialkyl methaneselenophosphonates provides a highly efficient route to the PCH(2)PCH(2)P backbone. This new development in selenophosphonate chemistry offers a great potential for further regioselective functionalization of polyphosphate mimics.

Synthesis and biological evaluation of fluorinated deoxynucleotide analogs based on bis-(difluoromethylene)triphosphoric acid

“…Although the synthesis of bis(methylene)triphosphoric acid 3 has been known for a long time (6,7), all attempts at its direct preparation from dialkyl methylphosphonate have failed (8). Michaelis-Arbuzov-type reactions have been shown to be useful in the preparation of nonfluorinated analogs (6,9).…”

“…Only a few methods for attaching low nucleophilicity phosphates to the 5′-carbon of a nucleoside are known (14,15). These methods include the Mitsunobu reaction (8,(16)(17)(18), couplings promoted by DCC and other dehydrating agents (19,20), electrophilic phosphorylation developed by Yoshikawa, Ludwig, and Eckstein employing 2-chloro-4H-1,3, 2-benzodioxaphosphorin-4-one (21)(22)(23)(24), nucleophilic cleavage of phosphoryl anhydride (25), reactions involving phosphoramidates (19,(26)(27)(28)(29)(30)), Blackburn's method employing nucleophilic substitution at 5′ position (31)(32)(33), and enzymatic phosphorylation (20,34,35). All of these methods lack versatility and their success depends on many factors, such as nucleophilicity/electrophilicity of the phosphate source, steric bulkiness, stability of the product under acidic or basic conditions, etc.…”

Two-headed tetraphosphate cap analogs are inhibitors of the Dcp1/2 RNA decapping complex

“…The O-to-F substitution at the terminal phosphate results in a smaller net negative charge and impairs H-bonding (Baranowski et al 2015). The bridging O-to-CH 2 substitution provides resistance to hydrolysis since the P-C bonds are remarkably stable, however, the inability to form H-bonds can deteriorate affinity to some proteins (Klein et al 2002;Grudzien et al 2006). The bridging imidodiphosphate modification is also highly resistant to hydrolysis by pyrophosphatases and better emulates the electronic properties of unmodified phosphatases, such as their charge distribution and H-bond accepting ability due to the higher electronegativity of nitrogen (Yount et al 1971).…”

Phosphonate analogues of nucleoside polyphosphates

“…Thus, if adenosine or guanosine is used as substrates for the Mitsunobu reaction the yields of the coupling are usually lower due to intramolecular nucleophilic attack of the activated 5´-position by a N 3 atom of the base. [82][83][84][85] Another possible side reaction involves formation of the 5´-hydrazo substituted compounds, which are most likely formed due to the rearrangement of an intermediate nucleoside-PPh3/DEAD complex. 85 Moreover, the Mitsunobu reaction is a poor choice if an incoming phosphonate substitute has several hydroxyl groups available for coupling.…”

“…[82][83][84][85] Another possible side reaction involves formation of the 5´-hydrazo substituted compounds, which are most likely formed due to the rearrangement of an intermediate nucleoside-PPh3/DEAD complex. 85 Moreover, the Mitsunobu reaction is a poor choice if an incoming phosphonate substitute has several hydroxyl groups available for coupling. 86,87 Nevertheless, in spite of these limitations, several recent innovations have significantly extended the scope and synthetic utility of the method.…”