Synthesis and antiviral activity of 5-thien-2-yl-2'-deoxyuridine analogs

Abstract

A number of 5-heteroaromatic-substituted 2'-deoxyuridines were synthesized from 5-iodo-2'-deoxyuridine using tetraorganotin reagents and palladium complexes as catalyst. The palladium-catalyzed cross-coupling reaction between 5-iodo-2'-deoxyuridine and stannylated heteroaromatics was optimized for the synthesis of the 5-thien-3-yl-2'-deoxyuridine and 5-furan-3-yl-2'-deoxyuridine. 5-(5-Iodothien-2-yl)-2'-deoxyuridine was used as starting material for the synthesis of 5-(5-methylthien-2-yl)-2'-deoxyuridine, 5-(5-vinylthien-2-yl)-2'-deoxyuridine, and 5-(5-ethynylthien-2-yl)-2'- deoxyuridine. 5-(5-Nitrothien-2-yl)-2'-deoxyuridine was synthesized using ceric ammonium nitrate as reagent. 5-(Isoxazol-5-yl)-2'-deoxyuridine was synthesized from 5-(3-oxopropyn-1-yl)-2'-deoxyuridine. Finally, 5-(5-chlorothien-2-yl)-beta-D-arabinofuranosyluracil and 5-(5-bromothien-2-yl)-beta-D-arabinofuranosyluracil were obtained by halogenation of 5-thien-2-yl-beta-D-arabinofuranosyluracil. Introduction of an alkyl substituent in the 5-position of the thienyl group of 5-thien-2-yl-2'-deoxyuridine or substitution of the 2-deoxyribofuranose ring by an arabinofuranose moiety gave decreased activity against HSV-1 and VZV replication when compared with the 5"-halogenated-5-thien-2-yl-2'-deoxyuridines. 5-(5-Bromothien-2-yl)-2'-deoxyuridine caused prompt healing of HSV-1 keratitis when administered as eye drops (0.2%) to rabbits.

Synthesis of Various 5-(5″-Substituted-3″-Bromophenyl)-2′-β-Deoxyuridines

“…After purification (eluent 18:2), the yield was 2.9 g (62%), In assays for HCMV activity, the lead compound 5-(3-bromophenyl)-2'-deoxyuridine was found to inhibit the cytopathogenic effects of the virus by about 75% at a concentration of 10 IJ,g mr' (Wellmar et al, 1996). In a HCMV ELISA, using viral antibodies as an endpoint, the 50% inhibitory concentration (E0 5 A number of 5-heteroaryl substituted 2'-deoxyuridine compounds have been reported to have potent anti HSV-1 activities (Wigerinck et al, 1991a;Wigerinck et al, 1991b;Wigerinck et al, 1993;Herdewijn, 1994). However, in contrast to 5-(2-E-bromovinyl)-2'-deoxyuridine (BVDU), the antiherpes activities of these compounds are dependent on both the cell type and virus strain used in the assay (Vrang and Johansson, unpublished data).…”

“…One approach could be to brominate the aryl unit of the corresponding 5-aryl-2,4-di-t-butoxypyrimidines or 5-aryluracils. This has recently been carried out with different 5-(heteroaryl) substituted 2'-deoxyuridines and arabinouridines (Wigerinck et al, 1993). However, the major disadvantage of this method is the lack of regioselectivity for the bromination.…”

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

“…10,11 Building on this principle, we have begun to explore new connectivities for these innovative nucleosides. 12,13 In this regard, coupling a fleximer base system to a carbocyclic "sugar" should prove advantageous. The carbocyclic modification has been proven to be a potent structural aspect of numerous modified nucleosides.…”

Relationship between structural properties and affinity for herpes simplex virus type 1 thymidine kinase of bromine substituted 5-heteroaromatic 2′-deoxyuridines

“…In an effort to try to improve the properties of existing 5-substituted pyrimidine nucleoside analogues we have synthesized several 5-heteroaromatic substituted congeners (Wigerinck et al, 1991a;Wigerinck et al, 1991b;Wigerinck et al, 1993). Many among them demonstrate potent anti-HSV-1 activity.…”