Synthesis and antiviral activity of 5-heteroaryl-substituted 2'-deoxyuridines.

The synthesis of 5-heteroaryl-substituted 2'-deoxyuridines is described. The heteroaromatics were obtained from three different 5-substituted 2'-deoxyuridines. Cycloaddition reaction of nitrile oxides on the 5-ethynyl derivative 1 gave the isoxazoles 4a-e. The thiazole derivatives 14a-c were obtained from the 5-thiocarboxamide 11, while 5-pyrrol-1-yl-2'-deoxyuridine (17) could be synthesized directly from 5-amino-2'-deoxyuridine. The compounds were evaluated for antiviral activity. Selective activity against herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) was noted for 5-(3-bromoisoxazol-5-yl)-2'-deoxyuridine (4c). The compound was inactive against herpes simplex virus type 2, cytomegalovirus, and thymidine kinase (TK)-deficient mutants of HSV-1 and VZV, which indicates that, most likely, its antiviral activity depends on phosphorylation by the virus-specified TK.

Synthesis and antiviral activity of 3'-heterocyclic substituted 3'-deoxythymidines.

Various 3'-deoxythymidine analogues with an heterocyclic five-membered ring in the 3'-erythro position have been synthesized. The pyrrol-1-yl (3) and the 1,2,4-triazol-4-yl (5) compounds were synthesized from 1-(3-amino-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine. The pyrazol-1-yl (16a), imidazol-1-yl (16b), and 1,2,4-triazol-1-yl (16c) derivatives were obtained by epoxide opening of the corresponding 1-(2,3-anhydro-beta-D-lyxofuranosyl)thymines followed by 2'-deoxygenation. Only the 3'-pyrrol-1-yl derivative showed marginal antiviral activity against human immunodeficiency virus.

5-(5-Bromothien-2-yl)-2'-deoxyuridine and 5-(5-chlorothien-2-yl)-2'-deoxyuridine are equipotent to (E)-5-(2-bromovinyl)-2'-deoxyuridine in the inhibition of herpes simplex virus type I replication.

2'-Deoxyuridines with a five-membered heterocyclic substituent in the 5-position were synthesized by palladium-catalyzed coupling reactions of 5-iodo-2'-deoxyuridine with the activated heteroaromatics. Further modification of the compound with the 5-thien-2-yl substituent gave 5-(5-bromothien-2-yl)-2'-deoxyuridine and 5-(5-chlorothienyl-2-yl)-2'-deoxyuridine. Both compounds show potent and selective activity against herpes simplex virus type 1 and varicella-zoster virus.

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

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.

Stereoelectronic properties of five anti-HSV-1 2'-deoxynucleosides analogues with heterocyclic substituents in the 5-position: a comparison with BVDU.

Structural and electronic characteristics of 5-(5-chlorothien-2-yl)-2'-deoxyuridine (I), 5-(furan-2-yl)-2'-deoxyuridine (II), 5-(5-bromofuran-2-yl)-2'-deoxyuridine (III), 5-(3-bromoisoxazol-5-yl)-2'-deoxyuridine (V) and 5-(isoxazol-5-yl)-2'-deoxyuridine (IV) have been determined and compared to the BVDU (VI) characteristics in order to explain their respective affinity for the herpes simplex virus type 1 thymidine kinase (TK). Molecular structure of 5-(5-chlorothien-2-yl)-2'-deoxyuridine has been obtained using single crystal X-ray crystallography. Electrostatic potential maps, energy and topology of frontier orbitals were computed at the ab initio MO STO-3G and STO-3G level. These studies reveal that the electrostatic potential energy maps are clearly dependent on the affinity of the compound for the enzyme.

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

The crystal structures of 5-(5-furan-2-yl)-2'-deoxyuridine (II), 5-(5-bromofuran-2-yl)-2'-deoxyuridine (IV) and 5-(3-bromothien-2-yl)-2'-deoxyuridine (V) have been studied in order to explain the different affinity of the compounds for the herpes simplex virus type 1 (HSV-1) thymidine kinase. These compounds present a variable affinity according to the position of the heteroatom substituting the five-membered ring. An unfavourable substitution in the five-membered ring for interaction with the HSV-1 thymidine kinase has been identified.

Mechanism of cytostatic action of novel 5-(thien-2-yl)- and 5-(furan-2-yl)-substituted pyrimidine nucleoside analogues against tumor cells transfected by the thymidine kinase gene of herpes simplex virus.

Several novel 5-substituted 2'-deoxyuridine (dUrd) analogues were evaluated as substrates for highly purified herpes simplex virus type 1 (HSV-1)-encoded thymidine kinase (TK) derived from HSV-1 TK gene-transfected murine mammary carcinoma FM3A cells, and human platelet thymidine (dThd) phosphorylase. The Ki of 5-(furan-2-yl)-dUrd, 5-(thien-2-yl)-dUrd and 5-(thien-2-yl)-dCyd for HSV-1 TK was 0.94, 0.71, and 1.32 microM, respectively. Inhibition was competitive with respect to the natural substrate dThd. With dCyd as substrate, the Ki of 5-(thien-2-yl)-dCyd for HSV-1 TK was 4.5 microM (Ki/Km = 0.17). In striking contrast with (E)-5-(2-bromovinyl)-dUrd, the 5-(thien-2-yl)- and 5-(furan-2-yl)-dUrd derivatives were not substrates for human dThd phosphorylase. 5-(Thien-2-yl)-dUrd, 5-(furan-2-yl)-dUrd and 5-(thien-2-yl)-dCyd were at least 100-fold more cytostatic to the HSV TK gene-transfected FM3A tumor cells than wild-type FM3A/0 cells. The viral TK expressed in the HSV-1 TK gene-transfected tumor cells merely acts as an activating enzyme, whereas thymidylate synthase serves as the target enzyme for the cytostatic action of the compounds. The novel 5-substituted dUrd analogues should be further pursued as candidate drugs in the treatment of HSV TK gene-transfected tumors.