Publications

We have previously reported the discovery and preliminary structure-activity relationships of a new class of inhibitors of varicella-zoster virus (VZV). These novel furanopyrimidine nucleosides bear unusual bicyclic base moieties and exhibit complete specificity for VZV. Limited in vitro cytotoxicity has been detected and the bicyclic nucleosides are now well established as a new family of potent antivirals. Our initial studies revealed an absolute requirement of a long alkyl side-chain, with an optimal chain length of C8-C10, for antiviral activity. Following further studies, we recently reported a significant enhancement of both antiviral potency and selectivity by the inclusion of a phenyl group within the alkyl side-chain of these compounds. The new lead p-alkylphenyl analogues displayed EC50 values below 1 nM versus VZV and selectivity index values >1000000. We herein report the synthesis and characterization of a further series of alkylaryl analogues bearing terminal phenyl groups with varying n-alkyl side-chain lengths. Synthesis of the target bicyclic systems involved the Pd-catalysed coupling of terminal acetylenes with 5-iodo-2'-deoxyuridine to give intermediate 5-alkynyl nucleosides which were then cyclized in the presence of copper (I) iodide. The current compounds display excellent selectivity for VZV with no detectable in vitro cytotoxicity but despite being chemically isomeric with the previous lead p-alkylphenyl analogues, the compounds reported herein exhibit only moderate antiviral activities. A possible correlation between antiviral activity and conformational freedom of the side-chain is discussed.

Abstract 2′‐Deoxy‐5‐(isothiazol‐5‐yl)uridine ( 12 ) was synthesized starting from 2′‐deoxy‐5‐iodouridine using a Pd‐catalysed cross‐coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2′‐Deoxyuridine 12 has a particular place among the 5‐heteroaryl‐substituted 2′‐deoxyuridines in that it has a high affinity for herpes simplex virus type 1 (HSV‐1)‐encoded thymidine kinase (TK) without antiviral activity. Biochemical studies revealed that 12 is a substrate for viral TK. We further investigated the interaction of 12 with the HSV‐1 thymidine kinase. The conformation of 12 in solution was established by NMR spectroscopy. The most stable conformer 12A has the S‐atom of the isothiazole ring placed in the neighbourhood of the C(4)O group of the pyrimidine moiety. The compound was docked in its most stable conformation in the active site of HSV‐1 TK and subjected to energy minimization. This demonstrated that the isothiazole moiety binds in a cavity lined by the side chains of Tyr‐132, Arg‐163, Ala‐167, and Ala‐168 and that the C(3) atom of the isothiazole moiety is located in close proximity of the phenolic O‐atom of Tyr‐132 and the aliphatic part of the Arg‐163 side chain.

The HIV-1-specific oxathiin carboxanilide derivative 1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)carbonyl]amino]benzoate (NSC 615985) (designated UC84) has potent activity against HIV-1(III B ) (50% effective concentration: 0.015 μg ml −1 ). UC84 was found to select for a 138-Lys mutant virus strain in HIV-1-infected CEM cell cultures. When the 138-Lys mutation was introduced solely in the p51 subunit of the p51/p66 reverse transcriptase (RT) heterodimer by site-directed mutagenesis, the enzyme proved 10-fold more resistant to UC84 than when the amino acid mutation was introduced solely in the p66 subunit of the p51/p66 RT heterodimer. These data provided clear evidence for a structural and functional role of the p51 subunit in the sensitivity/resistance of the enzyme to UC84. UC84 also proved to be virtually inactive against mutant HIV-1 strains containing the 100-lle, 106-Ala, 138-Lys or 181-Cys mutation in their RT. However, minor structural changes in the molecule, such as replacement of the oxygen of the amide moiety by sulfur, or the isopropyl ester moiety by cyclopentyl or a secondary butyl, or the methyl group of the oxathiin part by ethyl, made the compound markedly more inhibitory to one or several HIV-1 mutant strains. For example, compound 131 (1-methylethyl 2-chloro-5-[[(5,6-dihydro-2-methyl-1,4-oxathiin-3-yl)thioxomethyl]amino]benzoate was only 2-fold more active than the parent compound UC84 against wild-type HIV-1, but 30- to 100-fold more inhibitory to HIV-1 mutant strains that contained the 100-11e, 106-A1a, 138-Lys or 181-Cys in their RT. These findings should be taken into account when selecting suitable drug candidates for the treatment of HIV-1 infections, particularly those that have developed resistance to other non-nucleoside RT inhibitors (NNRTIs).

The 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) represent a recently discovered chemical class of non-nucleoside reverse transcriptase inhibitors that selectively block human immunodeficiency virus type 1 replication. In a search for a better understanding of their mode of binding and with the aim of obtaining novel lead compounds, a second series of TTD derivatives was synthesized and evaluated for antiviral activity. The design of the new compounds was based on a variety of chemical modifications which were carried out in the original prototype 20a (QM 96521). Substitution of a halogen at the meta position of the N-2 benzyl group resulted in an improvement of the antiviral activity by 1 order of magnitude. Compounds bearing at the N-4 position a cyanomethyl, propargyl, or benzyl substituent were found to be the most potent of the series. Modifying the thieno[3,4-e] ring fused to the 1,2,4-thiadiazine moiety to other heterocyclic ring systems decreased the potency. The results obtained in this investigation have provided new indications for the design of even more effective TTDs.

A novel compound, TTP-8307, was identified as a potent inhibitor of the replication of several rhino- and enteroviruses. TTP-8307 inhibits viral RNA synthesis in a dose-dependent manner, without affecting polyprotein synthesis and/or processing. Drug-resistant variants of coxsackievirus B3 were all shown to carry at least one amino acid mutation in the nonstructural protein 3A. In particular, three mutations located in a nonstructured region preceding the hydrophobic domain (V45A, I54F, and H57Y) appeared to contribute to the drug-resistant phenotype. This region has previously been identified as a hot sport for mutations that resulted in resistance to enviroxime, the sole 3A-targeting enterovirus inhibitor reported thus far. This was corroborated by the fact that TTP-8307 and enviroxime proved cross-resistant. It is hypothesized that TTP-8307 and enviroxime disrupt proper interactions of 3A(B) with other viral or cellular proteins that are required for efficient replication.

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The effect of intralesional injections of cidofovir, a nucleotide analog with potent in vitro activity against human herpesvirus 8 (HHV-8), was studied in vivo in an HIV-negative patient with classical Kaposi's sarcoma (KS). After five weekly injections of the drug, no clinical, histological, immunohistological, or virological changes could be detected in comparison with saline-injected lesions. These findings suggest that, once the KS tumor has developed, active viral replication is no longer involved in the pathogenesis of the disease. Alternative hypotheses are that HHV-8 replication in blood-borne cells may foster growth of spindle cells in the skin, or that blocking HHV-8 may not affect existing lesions but may prevent new lesions from developing.

Derived from the structure of 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), 2,3-diaryl-1,3-thiazolidin-4-one derivatives became a novel class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Under the guidance of continuous structure-activity relationship (SAR) analysis and molecular modeling, various structural modifications were carried out on nearly all the positions of the thiazolidin-4-one nucleus. Some of the derivatives proved to be highly effective against HIV-1 replication at 10-40 nanomolar concentration ranges with minimal cytotoxicities. In this article, the whole development of 2,3-diaryl-1,3-thiazolidin-4-one series from the discoveries to recent advances, their panoramic SAR studies and binding modes based on molecular modeling were reviewed, and also some enlightenments for further investigation were presented.