"Reverse Fleximers": Introduction of a series of 5-substituted carbocyclic uridine analogues

Abstract

Nucleosides are ubiquitous in biological systems and as such, have been a focus of medicinal chemistry research in the search for new and potent therapeutic compounds. There are a number of modified nucleosides on the market, however increasing reports of resistance by mutation of either the enzyme binding site or the pathway that they are designed to interrupt are surfacing. As shown in recent reports, a candidate that can change conformation and still maintain recognition by the target enzyme would be highly desirable, and it is for this reason that flexible substrates have recently been sought as potential therapeutics. With this goal in mind, we have begun investigation into novel flexible scaffolds capable of overcoming viral resistance mechanisms resulting from binding site mutations.

Practical synthesis of 6-aryluridines via palladium(II) acetate catalyzed Suzuki–Miyaura cross-coupling reaction

“…5-Aryluridines have been extensively utilized as fluorescent probes for the studies of electron-transfer in DNA, 1e10 or as biosensors for the detection of uridine-related protein targets. 11 In addition, 5-aryluridines represent a series of dimensional analogs of thymidine 12e19 or flexible ring-split analogs ('fleximers') of purine nucleosides, 20 which have been used as spatial probes to investigate related enzymes or receptors. The synthesis of 5-aryluridines from 5-halouridines was readily achieved by the palladium-catalyzed cross-coupling reactions in which both SuzukieMiyaura 1e6,11e13, 21,22 and Stille 7e10,14e20,22 reactions were applicable.…”

New, Efficient Approach for the Ligand-Free Suzuki–Miyaura Reaction of 5-Iodo-2′-deoxyuridine in Water

“…The synthesis of 5-aryluridines and the corresponding 2′deoxyuridines was usually readily achieved by the palladium-catalyzed Suzuki-Miyaura 10,17,18 or Stille reaction in organic solvents, starting from protected 5-halouridines and 2′-deoxyuridine, respectively. 9,12,14,[19][20][21][22][23][24][25][26][27][28][29] In regard to the development of green chemistry, academic and industrial research has permitted the establishment of a catalytic Suzuki-Miyaura protocol based on atom economy, less hazardous chemical syntheses, and safer solvents and auxiliaries. In this respect, the Suzuki-Miyaura reaction has been developed with or without ligand in safe, economical and environmentally benign aqueous media such as a cosolvent mixture in water 30,31 or neat water.…”

1-Benzyl derivatives of 5-(arylamino)uracils as anti-HIV-1 and anti-EBV agents

“…2), some of which have exhibited potent biological activity. [19][20][21][22][23][24] Similar to Tenofovir 25 and Etravirine, [26][27][28] both FDA-approved HIV-1-RT inhibitors, our compounds' inherent flexibility allows them to overcome resistance mechanisms related to point mutations. 29,30 The concepts of conformational flexibility and positional adaptability, or the ability to 'wiggle and jiggle' in a binding site when confronted with an active site mutation have now been shown [26][27][28] to be critical for avoiding resistance mechanisms for non-nucleoside HIV-1-RT inhibitors, thus provide additional impetus for our approach.…”