Carbocyclic analogs of 5-substituted uracil nucleosides. Synthesis and antiviral activity

Abstract

Carbocyclic analogues of 3'-deoxyuridines, 3'-deoxyuridines, and uridines with substituents at position 5 of the uracil moiety were prepared by direct halogenation (5-bromo and 5-iodo groups) and by displacement of the 5-bromo group by amino and substituted-amino groups. The analogue of 5-(hydroxymethyl)uridine was prepared via reaction of the isopropylidene derivative of the uridine analogue with paraformaldehyde. The carbocyclic analogues of thymidine and of 5-bromo-, 5-iodo-, and 5-(methylamino)-2'-deoxyuridine were highly active in vitro against herpes simplex virus, types 1 and 2. The corresponding analogues of 5-substituted 3'-deoxyuridines and of 5-substituted uridines were not active in this assay.

Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice

“…However, this approach involves the use of a second drug in combination with ara-A or ara-AMP, and deleterious problems could possibly arise from the marked inhibition of adenosine deaminase activity in a patient treated with such combinations. An (1,22,26). The chemical synthesis of cyclaradine was facilitated through the use of a simple, high-yield route to carbocyclic nucleoside analogs developed by Daluge and Vince (7,8).…”

Carbocyclic nucleosides

“…Chronologically, the first compound described was the thymidine isostere C-Thy (57b) which was synthetically approached by the Prins reaction starting with known 1-(3-~yclopentenyl)thyrnidine (78 The carbocyclic uridine andogue (C-Urd, 56a) was first reported by Holy,20,64 but since the structure of his starting C-rib-NH2 was later confirmed to be erroneous,25 the isolated compound was rather an isomer of C-Urd of yet unknown structure.2 The compound with the correct structure was prepared later by an analogous procedure used for the synthesis of C-Thy that started with authentic C-rib-NH2 (6).65, 66 The generality of Shealy's method permitted ready access to many carbocyclic sugar isosteres by simply starting with the appropriate aminocyclopentane (57-62). 13,15,65,66 In addition, compounds with inverted configuration at C-2' and C-3' (59, 60, and 61) were obtained by hydrolysis of the corresponding 2,2'-anhydronucleosides and 2,3'-anhydronucleosides (e.g.…”

“…The 5-(hydroxymethy1)carbocyclic uracil 56h was obtained from the acetonide of C-Urd after treatment with paraformaldehyde. 66 All carbocyclic uracil nucleosides with isosteric ring moieties of ribose, 2'-deoxy, and 3'-deoxyribose (56a, 57a, 58a) were inactive in culture against KB as well as L1210 cells. 65 The very attractive 5-F-C-dUrd (57c), which is chemically stable and does not release 5-F-Ura, was anticipated to be more specific than 5-F-dUrd.…”

Regiospecific synthesis of cyclopentane analogs of (2′- and 3′-deoxy-threo-pentofuranosyl)-uracil and -2-thiouracil nucleosides

“…The synthetic routes also provide the possibility of regiospecific synthesis of cyclopentane analogs of nucleosides having the "deoxyribo" configurations, by an inversion of configuration at C-2' or C-3' in the corresponding "deoxylyxo" analogs. Analogs having the "2-deoxyribo" configuration have been found to be biologically active in a variety of systems (2,25 …”

“…A large number of cyclopentane analogs of both purine and pyrimidine nucleosides have been synthesized and many have shown antiviral and (or) anticancer activity (see, for example, refs. [2][3][4][5][6][7].…”