Synthesis and Biological Activity of Selected Carbocyclic Nucleosides

Abstract

Nucleoside analogues are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Replacement the oxygen of furanose ring of a nucleoside by a CH 2 unit results in carbocyclic nucleoside analogues. Carbocyclic nucleosides have emerged as targets of intense investigation due to their potent biological activity and greater metabolic activity and stability to nucleoside phosphorylases than the corresponding carbohydrate counterpart. Among these, aristeromycin (1), neplanocin (2), abacavir (3), lobucavir (4), synguanol (5) or the newly FDA-approved anti-HBV Baraclude Ò (6, Entecavir) ( Figure 15.1) are a few of the carbocyclic nucleosides that are useful antiviral drugs.The cellular processing and mechanism of action of carbocyclic nucleosides are, in general, similar to those of conventional nucleosides. They may undergo progressive phosphorylation to the corresponding mono-, di-, and triphosphates, and any of these activated forms may interact with natural cellular processes (Figure 15.2). On occasion, the interaction is innocuous and has little or no effect upon cell viability, but very often a significant inhibition of essential biochemical reactions occurs and in these cases measurable effects will be observable.One class of cellular enzymes to which carbocyclic nucleosides are not susceptible is the nucleoside phosphorylases, as a consequence of which they are extremely stable towards sugar-base cleavage. Most of those carbocyclic nucleosides which have been studied intensively are active as inhibitors of a viral enzyme (mainly a polymerase). Experience has shown that the essential structural features of carbocyclic nucleosides which must be retained are: the ability of the base to engage in base pairing with its DNA partner, and the presence of a 5 0 -hydroxyl group (or equivalent) which is capable of phosphorylation. The remainder of the sugar component can be regarded as a scaffold which ensures that the base pairing functionality and the 5 0 -phosphate (or phosphonate) are well distributed in space. The carbocyclic nucleosides do not have the same conformational data as the parent nucleosides; rather, in all cases they Modified Nucleosides: in Biochemistry, Biotechnology and Medicine. Edited by Piet Herdewijn

The first intermolecular interrupted imino-Nazarov reaction: expeditious access to carbocyclic nucleoside analogues

“…Carbocyclic nucleosides represent an emerging class of privileged therapeutic compounds which exhibit interesting biological properties. 1 , 2 Substitution of endocyclic oxygen by a methylene unit in a carbocyclic nucleoside derivative imparts greater stability in the C–N pseudoglycosidic bond towards both chemical and enzymatic processes as compared to the parent nucleoside counterpart. 2 Some examples of naturally-occurring and synthetic carbocyclic nucleosides with potent pharmacological activity, such as aristeromycin, 3 neplanocin A, 4 carbovir 5 and abacavir, 6 are depicted in Fig.…”

A Stereocontrolled Synthesis of a Phosphorothioate Cyclic Dinucleotide-Based STING Agonist

“…The filtrate was concentrated to dryness to give compound 5 as a white solid (21.7 g, 90% yield). Data for compound 5: 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35 (s, 1H), 8.13 (s, 1H), 7.28−7.15 (m, 18H), 4.78 (q, J = 9.0 Hz, 1H), 4.58 (t, J = 5.3 Hz, 1H), 3.48 (t, J = 5.5 Hz, 2H), 3.10 (m, 2H), 2.97 (m, 1H), 2.45 (td, J = 7.9, 10.3 Hz, 1H), 2.21 (q, J = 10.1 Hz, 1H), 2.09 (m, 1H); (7). To a 1 L round-bottom flask was added compound 6 (33.0 g, 37.8 mmol), dissolved in anhydrous CH 3 CN (150 mL), and the mixture was concentrated.…”

“…6 Interestingly, BMT-390025 is characterized as a CDN bearing two bridging phosphorothioate linkages, which impart four potential phosphorus diastereoisomers. Seven additional carbon-based stereocenters come from the "linear" tricyclic guanosinederived nucleoside and the lobucavir-inspired 7 cyclobutane, which constitute the novel design elements of this complex molecule.…”

Synthesis and Reactivity of Spirocarbocycles as Scaffolds for Nucleoside Analogues

“…These nucleoside isosteres are characterized by an increased metabolic stability when compared to the riboside analogues as they are not recognized by, for example, nucleoside phosphorylases and hydrolases that otherwise can cleave the glycosidic bond . Consequently, the synthetic design and biological properties of various carbocyclic nucleosides have been well documented, with applications of this compound class in the therapeutic areas of antiviral and anticancer drug discovery research. Important examples of carbocyclic nucleosides that have been marketed include the antiviral drug abacavir ( 1 ), which is a highly potent nucleoside reverse transcriptase inhibitor used as an anti-HIV medication, and entecavir ( 2 ), used in the treatment of patients suffering from hepatitis B infection (Figure ).…”