“Reverse” Carbocyclic Fleximers: Synthesis of a New Class of Adenosine Deaminase Inhibitors

Abstract

A series of flexible carbocyclic pyrimidine nucleosides has been designed and synthesized. In contrast to previously reported “fleximers” from our laboratory, these analogues have the connectivity of the heterocyclic base system “reversed”, where the pyrimidine ring is attached to the sugar moiety, rather than the five membered imidazole ring. As was previously seen with the ribose fleximers, their inherent flexibility should allow them to adjust to enzyme binding site mutations, as well as increase the affinity for atypical enzymes. Preliminary biological screening has revealed surprising inhibition of adenosine deaminase, despite their lack of resemblance to adenosine.

Flexibility—Not just for yoga anymore!

“…In contrast, the second series, denoted as “proximal” fleximers, were much more facile to achieve since the requisite substitution patterns on the two heterocyclic pieces needed for metal catalyzed cross coupling methods were available. 23 , 27 , 28 This allowed for use of Stille, Suzuki and other organometallic coupling reactions as depicted in Figure 5 . 23 , 29 , 30 …”

“…The connectivity was via the pyrimidine ring with the five-membered ring as the appendage ( Figure 11 ) yielding the “reverse” fleximers. 27 , 45 The inspiration for this change in connectivity came from 2′-deoxy nucleoside analogues first published in 1991 by Herdewijn et al. 46 – 48 Some of these showed impressive activity against herpes simplex virus (HSV-1) and varicella zoster virus (VZV).…”

Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1

“…For some time, the Seley-Radtke group has designed and synthesized various classes of flexible purine nucleos(t)ides, or “fleximers”. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 These novel nucleosides were designed to investigate how flexibility in the nucleobase could potentially affect receptor-ligand recognition and function. In addition, their flexible design allows them to overcome issues with binding site mutations thus retaining their activity.…”

“…To date, fleximers have shown key advantages over the corresponding purine-base nucleosides. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 For example, the distal guanosine fleximer (Flex-G, Fig. 1 ) proved to be an inhibitor of S -adenosyl- l -homocysteine hydrolase by adapting a syn conformation, thereby placing the exocyclic amino group such that it mimicked the amino group from an adenosine nucleobase.…”

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

“…Indeed, the assembly of the triazole ring with various substituents confers to the final compound high flexibility. Initially reported by K. Seley-Radtke’s group, the replacement of the nucleobase by a “flexi-moiety” where the imidazole ring and a six-membered heterocycle is linked through a C–C bond lead to new derivatives behaving as nucleosides and even as enzyme inhibitors [ 11 – 13 ]. The inherent flexibility of the corresponding nucleobase-mimics allows to accommodate steric and electronic clashes encountered in protein binding sites and to interact with other amino acids.…”