Antiviral Activity of Bicyclic Pyrimidine Nucleosides

Abstract

SummaryA number of pyrimidine nucleosides, which may show two hydrogen bonding modes, have been prepared and tested for antiviral activity against a series of viruses. Whilst none of the compounds described showed significant activity against human immunodeficiency virus (HIV), the bicyclic 2'-deoxynucleoside,

Parallel Solution-Phase Synthesis of 4-Dialkylamino-2-methylsulfonyl-6-vinylpyrimidines

“…In fact, protection at N-1 or N-3 positions and Pd-assisted cross-coupling reaction are required to obtain 6-vinyl derivatives in moderate to good yield . Moreover, the contemporary introduction of both a vinyl moiety at C-6 and an amino group at C-4 positions of pyrimidine bases requires more than one synthetic step: C-6 formylation and subsequent Wittig reaction are used to elaborate the 6-vinyl group, while the introduction of a leaving group in C-4 and its subsequent nucleophilic displacement are necessary to introduce the C-4 dialkylamino moiety . Chemical evidence as well as some infrared and ultraviolet data led us to hypothesize a concerted intermolecular four-center mechanism for this unprecedented rearrangement reaction …”

Synthesis and Antiviral and Cytostatic Evaluations of the New C-5 Substituted Pyrimidine and Furo[2,3-d]pyrimidine 4‘,5‘-Didehydro-l-ascorbic Acid Derivatives

“…The 5-(2-substituted) vinyl-2‘-deoxyuridines, in particular ( E )-5-(2-bromovinyl)-2‘-deoxyuridine, have emerged as potent and selective inhibitors of herpes virus replication, particularly against HSV-1 (herpes simplex virus type 1) and VZV (varicella-zoster virus). − Pyrimidine nucleosides containing C-5 alkynyl groups have been shown to possess significant antiviral and/or anticancer properties . The 5-alkynyluracil nucleosides with a longer alkynyl chain at the C-5 position exhibited appreciable antiviral activity in contrast to the corresponding alkyl derivatives that showed decreasing antiviral activity with increasing C-5 side chain length. − Moreover, bicyclic nucleoside analogues represent highly specific and extremely potent antiviral agents. − SAR studies on furo[2,3- d ]pyrimidine nucleoside analogues have shown that the length of the alkyl chain at the C-6 position of the furopyrimidine ring plays a crucial role in their anti-VZV potency. Compounds with shorter alkyl chains (≤C 6 ) had little or no activity, while those with a C7 or C11 side chain had moderate activity, and those with C8 to C10 alkyl chains had the highest potency. − We have reported that some pyrimidine and purine derivatives of 4‘,5‘-didehydro-5‘,6‘-dideoxy- l -ascorbic acid exerted pronounced cytostatic activities against malignant tumor cell lines. − Recently we have also reported that some C-5 substituted pyrimidine derivatives of l -ascorbic acid exhibited selective albeit slight inhibitory activity against certain human tumor cell lines and moderate but not highly specific inhibitory potential against herpes simplex viruses type 1 and 2, vaccinia virus, and Punta Toro virus .…”

“…[13][14][15][16] Moreover, bicyclic nucleoside analogues represent highly specific and extremely potent antiviral agents. [17][18][19] SAR studies on furo [2,3-d]pyrimidine nucleoside analogues have shown that the length of the alkyl chain at the C-6 position of the furopyrimidine ring plays a crucial role in their anti-VZV potency. Compounds with shorter alkyl chains (eC 6 ) had little or no activity, while those with a C7 or C11 side chain had moderate activity, and those with C8 to C10 alkyl chains had the highest potency.…”

“…[22][23][24] Recently we have also reported that some C-5 substituted pyrimidine derivatives of L-ascorbic acid exhibited selective albeit slight inhibitory activity against certain human tumor cell lines and moderate but not highly specific inhibitory potential against herpes simplex viruses type 1 and 2, vaccinia virus, and Punta Toro virus. 25 These results prompted us to synthesize a series of the novel C-5 pyrimidine derivatives of L-ascorbic acid containing an acetylene with longer side chain and p-alkylphenyl acetylene (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), and variously C-6 substituted furo [2,3-d]pyrimidine (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) moiety (Figure 1). The principal aim of this study was to evaluate the cytostatic and antiviral potencies of this class of novel compounds.…”

“…Reaction of IUAA with various terminal alkynes under Sonogashira conditions gave 5-substituted uracil derivatives 1-11 (Scheme 1). The targeted 6-alkylfuro [2,3-d]pyrimidine-2-one L-ascorbic acid derivatives (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) were synthesized by Sonogashira coupling of terminal alkynes with IUAA and copper(I)-promoted in situ cyclization. 30,34 These fused bicyclic pyrimidine analogues were prepared through an O-heteroannulation process using base and CuI as a catalyst (Supporting Information, Scheme S1).…”