2′‐O‐Alkyl Derivatives and 5′‐Analogues of 5‐Aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside (AICAR) as Potential Hsp90 Inhibitors

Abstract

Some selective preparations of AICAR-related compounds modified at the 2Ј-or 5Ј-position of the ribose moiety are reported herein. In particular, 5Ј-azido, 5Ј-amino, 5Ј-O-benzyl and a series of 2Ј-O-alkylated AICAR derivatives have been synthesized. These compounds were derived from appropriately functionalized inosines by opening the pyrimidine ring at the hypoxanthine residue. The target derivatives were designed with the purpose of studying the effect of AICAR

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

“…In the initial step, inosine was O ‐acylated for selective MEM group introduction and then deacylated with NH 3 /MeOH prior to ring opening for better solubility in water. Similarly, the acid labile 5‐ O ‐trityl‐ 45 b , [36] 3‐deoxy‐3‐ C ‐methyl‐ 45 c , [42] 5‐azido‐5‐deoxy‐2,3‐ O ‐isopropylidene‐ 45 d [43] protected inosines and arabinosyl hypoxanthine ( 45 e ) [44] – could be transformed to AICAR analogues. The Yamamoto group also demonstrated a synthesis of 2‐aryl‐AICARs 45 f – l .…”

Synthesis of New Acadesine (AICA-riboside) Analogues Having Acyclic d-Ribityl or 4-Hydroxybutyl Chains in Place of the Ribose

“…The AMPK pathway is also implicated in the regulation of cell proliferation and activation by AICAR could result in pro-apoptotic effects [18,19]. In particular, AICAR has been revealed to also be an antagonist of the protein Hsp90, a chaperone that regulates the correct interaction between proteins [20]. In such tumors Hsp90 is over-expressed, promoting aberrant cell survival and reproduction even in hostile environments [21].…”

Protein design: from computer models to artificial intelligence

“…Computer‐based methods have had a fundamental role in the field of small molecule and structure design and, considering the incredible pace at which hardware and software innovations are advancing, we can arguably foresee a decisive role for them in the evolution of new (nonnatural) functions, whereby biophysical chemistry models are more and more integrated to information science approaches . In this review, we briefly discuss some of the basic principles and most relevant achievements in computational protein design ranging from monomer design to self‐assembling systems, and then we focus on advances in the design of functions (Figure ).…”

“…[2][3][4] While the design of new structures has reached a predictive stage, the design of new functions still represents a difficult and exciting challenge as well as the most rigorous way of testing our actual understanding of how proteins really work. [4][5][6][7][8][9] Computer-based methods have had a fundamental role in the field of small molecule and structure design [10][11][12][13][14][15] and, considering the incredible pace at which hardware and software innovations are advancing, [16][17][18][19] we can arguably foresee a decisive role for them in the evolution of new (nonnatural) functions, whereby biophysical chemistry models are more and more integrated to information science approaches. 20 In this review, we briefly discuss some of the basic principles and most relevant achievements in computational protein design ranging from monomer design to self-assembling systems, and then we focus on advances in the design of functions (Figure 1).…”