Synthesis of 5‐Aminoimidazole‐4‐Carboxamide Riboside (AICAR) and Its Derivatives Using Inosine as Starting Material

Abstract

This unit contains four basic protocols describing the synthesis of 5-aminoimidazole-4-carboxamide riboside (AICAR), 5-aminoimidazole-4-carboxamide riboside (ZPM), their 4-N functionalized derivatives, and two sugar-modified analogs of AICAR. The first and second basic protocols reveal the importance of solid-phase synthesis to obtain novel AICAR and ZMP imidazole-modified analogs in a short time, whereas the third and fourth basic protocols allow for the rapid preparation of 5'-F-AICAR and D-ribityl AICA.

Applications of Purine Ring Opening in the Synthesis of Imidazole, Pyrimidine, and New Purine Derivatives

“…The inosines bound at the 5' position were also suitable for . [54,[77][78][79][80] Another ring opening method for substrates on solid support involves anchoring of ribose through a 2',3'-O-phydroxybenzylidene motif to MMT linker. 5'-O-TBDPS protected inosine (73) was first condensed with p-hydroxymethylbenzaldehyde dimethylacetal and bound to solid support via a MMTCl linker to form the key intermediate 70.…”

“…Finally, all acidlabile groups: MMT, acetal, TMS, and cyanoethyl were cleaved with 2 % TFA in DCM, providing inosine 73 and AICAR mono-phosphate (ZMP) analogues 74 in good yields (Scheme 13). [65,79,81,82] Various sulfonyl substituents (Ms, Tf, Ts, Ns, pNs, DNs, pentafluorobenzenesulfonyl, mesitylenesulfonyl) have been investigated as potential EWG for N-1 substitution in S N (ANRORC) by Ariza. [50] The formation of adenosine 78 was observed when 2,4-dinitrobenzenesulfonyl group (DNs) was used.…”

New Linear Precursors of cIDPR Derivatives as Stable Analogs of cADPR: A Potent Second Messenger with Ca2+-Modulating Activity Isolated from Sea Urchin Eggs

“…The strong 2,4-dinitrophenyl electron-withdrawing group makes the C2 purine atom very reactive towards amino-alcohols 7a – c , affording high yields (70–84%) of N1 ω -hydroxyalkyl inosines ( 8a-c ) [43,44,45,46], through a mechanism that we have studied in detail [47,48]. In particular, the nucleophilic addition of the amino group to the C2 purine atom leads to the pyrimidine ring opening; then, the same amino group attacks the imidazo 4-carboxamide functionality, reclosing the pyrimidine ring with the 2,4-dinitroaniline displacement.…”

5′-Chloro-5′-deoxy-2′,3′-O-isopropylidene-6-fluoro nebularine

“…The AMPK pathway is also implicated in the regulation of cell proliferation, and activation by AICAR could result in pro-apoptotic effects [10]. Given the importance of such a molecule, the synthesis of novel AICAR analogues is an appealing goal to better understand its mechanism of action [11][12][13][14][15]. Considering AICAR's low intestinal absorption and poor penetration of the blood-brain barrier, we synthesized a more lipophilic analogue, where the 5′-OH group was replaced by a fluorine atom (2, 5′-F-AICAR) [16].…”