Molecular Conformation Correlation to Activity Against Herpes Simplex Virus of (E)-5-(2-Bromovinyl)-2’-Deoxycytidine and 5-Methoxymethyl-2’-Deoxycytidine Analogs: Short-Review
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2019, Vol 13, Issue 5
Abstract
Analogs of (E)-5-(2-bromovinyl)-2’-deoxycytidine (BrVdCyd) (1) and 5-methoxymethyl-2’-deoxycytidine, MMdCyd (2) by substitution at N4 were synthesized to impart resistance against deamination. The anti HSV-1 activity and solution conformation of these analogs were determined. N4-Acetyl-BrVdCyd (3) was a potent inhibitor of HSV-1 replication while N4-propanoyl-BrVdCyd (4) had good activity and N4-butanoyl-BrVdCyd (5) had only low activity against HSV-1 replication. N4-Methyl-BrVdCyd (6) was devoid of activity against HSV-1. In the MMdCyd analog series, N4-butanoyl-MMdCyd (9) was a potent inhibitor of HSV-1 replication while N4-propanoyl-MMdCyd (8) and N4-acetyl-MMdCyd (7) had good activity against HSV-1 replication. N4-Methyl-MMdCyd (10), N4-methoxy-MMdCyd (11) and N4-phenyl-MMdCyd (12) were devoid of activity against HSV-1. Conformational correlation to anti HSV-1 activity or the lack of it is presented in this short review. The antimetabolites (E)-5-(2-bromovinyl)-2’-deoxycytidine (BrVdCyd) (1) and 5-methoxymethyl-2’-deoxycytidine, MMdCyd (2) are selective and potent antiherpes agents with low cytotoxicity [1,2,3]. The antiviral activity of BrVdCyd (1) and MMdCyd (2) is influenced by the cytidine/deoxycytidine (Cyd/dCyd) deaminase and deoxycytidilate (dCMP) deaminase content of the cell lines used for antiviral assays [1]. When deamination is prevented, both (1) and (2) are potent inhibitors of herpes simplex virus type 1 (HSV-1). The IC99 of BrVdCyd (1) (concentration required to reduce the yield of infectious virus obtained 72 h after infection by 99% relative to control cultures) was 1.6 μM when (1) was used in combination with tetrahydro-deoxyuridine (H4dUrd; an inhibitor of both dCyd and dCMP deaminases) (1). BrVdCyd (1) is also a good inhibitor of varicella zoster virus (VZV) replication [1]. Previous studies have shown that resistance to deamination for cytidines can be accomplished by structural modifications of the cytidine molecule [3-8]. Therefore, systematic investigations on the development of 5-substituted deoxycytidine analogs of (1) and (2) resistant to deamination were initiated. The rationale is that deoxycytidine analogs resistant to deamination would retain selectivity and metabolic stability thus simplifying HSV-1 treatment regimens. Therefore, N4-substituted derivatives of (E)-5-(2-bromovinyl)-2’-deoxycytidine (BrVdCyd) and 5-methoxymethyl-2’-deoxycytidine (MMdCyd) were synthesized to confer resistance to deamination, to improve delivery of the antimetabolite and to determine the bulk tolerance of the viral kinase to the N4-substituents of the cytosine moiety. The molecular conformation in solution was determined by NMR spectroscopy and the activity against herpes simplex virus type 1 (HSV-1) was determined using A549 cells. Compounds (3) and (4) were also found to be 100 times more potent and selective inhibitors of the varicella zoster virus (VZV) compared to the widely used antiviral drug acyclovir [9]. Chemical structures for compounds (1 - 12) are shown in Figure 1. The effectiveness of compounds (3-12) as inhibitors of HSV- 1 (McIntyre strain) replication was determined by the plaque reduction assay using A549 cells. The parent compounds BrVdCyd (1) and MMdCyd (2) were used as a positive control. N4-Acetyl- BrVdCyd (3) was significantly more active (ED50 = 0.01 μM) than its parent compound BrVdCyd (1) (ED50 = 0.61 μM), N4- propanoyl-BrVdCyd (3) was a good inhibitor of HSV-1 replication (ED50 = 0.12 μM) and N4-butanoyl-BrVdCyd (4) (ED50 = 6.00 μM) was a poor inhibitor compared to their parent compound (1). N4- Methyl-BrVdCyd (5) was devoid of activity (ED50 > 1024 μM). All compounds have low cytotoxicity and can be considered essentially nontoxic as measured by the CC50 (cytotoxic concentration required to reduce cell growth by 50% using confluent monolayers of A549 cells). Table 1 shows the antiviral activity data for all compounds with acyclovir’s activity added for comparison.
Authors and Affiliations
Wajdi Michel Zoghaib
Keywords
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- EP ID EP593794
- DOI 10.26717/BJSTR.2019.13.002471
- Views 132
- Downloads 0
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