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Structure/anti-herpes activity studies of pyrimidine nucleoside analogs



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Earlier studies have shown that 5-methoxymethyl-2$\sp\prime$deoxycytidine (MMdCyd (18)) and (E)-5-(2-bromovinyl)-2$\sp\prime$-deoxycytidine (BrVdCyd (17)) are potent and selective inhibitors of Herpes simples virus type-1 (HSV-1) replication with a high therapeutic index.1 The antiviral potency of BrVdCyd (17) and especially MMdCyd (18) against HSV-1 is greatly increased in the presence of tetrahydro deoxyuridine (H4dUrd (13)), an inhibitor of both Cyd/dCyd deaminase and deoxycytidylate (dCMP) deaminase.1 A major drawback for the therapeutic use of compounds in the cytidine (Cyd)/deoxycytidine (dCyd) family of derivatives is their tendency to undergo deamination in the presence of deaminating enzymes present in blood and mammalian cells.2 Deoxycytidine analogs resistant to deamination would have the advantage of simplifying treatment regimens as well as maintaining other advantages such as metabolic stability and selectivity since these drugs will be anabolized in virus infected cells bydCyd/dCMP kinase pathway. The principal goals and objectives of this research program were to synthesize deaminase resistant analogs of BrVdCyd (17) and MMdCyd (18) and to have some understanding of optimal conformational parameters essential for antiherpes activity. Analogs of MMdCyd (18) synthesized are: N4-acetyl-MMdCyd (30), N4-propanoyl-MMdCyd (31), N4-butanoyl-MMdCyd (32), N4-pivaloyl-MMdCyd (33) and N4-benzoyl-MMdCyd (34); N$\sp4,N\sp4$-dimethyl-MMdCyd (43), N4-phenyl-MMdCyd (44), N4-benzyl-MMdCyd (45), N4-methoxy-MMdCyd (54), N4-hydroxy-MMdCyd (55), N4-acetyl-N4-methyl-MMdCyd (57) and 3,4-etheno-MMdCyd (94). Analogs of BrVdCyd (17) synthesized are: N4-methyl-BrVdCyd (101), N4-acetyl-BrVdCyd (95), N4-propanoyl-BrVdCyd (96) and N4-butanoyl-BrVdCyd (97). Six of these analogs had anti HSV-1 activity, and were more potent than their parent compounds MMdCyd (18) and BrVdCyd (17). These active analogs are 30, 31, 32, 95, 96 and 97. The rest of the analogs were inactive. Stability studies of N4-acyl derivatives of MMdCyd (18) and BrVdCyd (17) at different pH values indicate that these analogs are stable in the range of pH 3 to pH 9. The 2-imino-5-methoxymethyl-2$\sp\prime$-deoxyuridine (2-imino-MMdUrd (66)) and 2-imino-5-methoxymethyl-2$\sp\prime$,3$\sp\prime $-didehydrodideoxycytidine (2-imino-MMddCyd (90)) analogs were prepared and were devoid of activity against HSV-1. Systematic conformational analysis by NMR spectroscopy of these nucleosides was used to identify the hypothetical pharmacophoric pattern that binds with the receptor (The skeleton of a pyrimidine deoxynucleoside substrate has four major modes of conformational flexibility).3 Analogs with the N4-substituent proximal to C5 and an anti glycosidic torsional preference were active against HSV-1. In contrast, analogs with the N4-substituent proximal to N3 or with a syn glycosidic torsional preference were inactive against HSV-1. The furanose population was in the range of 40/60 and 45/55 north/south distribution for all compounds. The g$\sp{+}$ exocyclic rotamer population was predominant (45-57%) for all compounds also. Thus this study could not conclude whether a correlation exists between antiviral activity and these two conformational parameters. Optimum geometrical features of a nucleoside required for recognition by the viral-induced kinase for biological activity have been determined.





Doctor of Philosophy (Ph.D.)







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