A New Synthesis of the Potent and Selective Anti-Herpesvirus Agent (S)-1-[3-Hydroxy-2-(Phosphonylmethoxy)Propyl]Cytosine

Abstract

A new synthetic approach to (S)-l-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (3, (S)-HPMPC) is based on coupling of the heterocyclic moiety with a glycerol-derived side chain, followed by introduction of the phosphonylmethyl ether group.Acyclic analogues of naturally-occurring nucleosides represent an For example, the 2 -deoxyguanoimportant class of 'antiviral agents.' sine analogue, acyclovir (1, ACV), has good activity against herpes simplex viruses (HSV) and varicella-zoster virus (VZV), and has been used extensively for treatment of these viral infections with minimal side effects.2 is particularly effective against cytomegalovirus (CMV) and has recently been approved for the treatment of CMV retinitis in AIDS patients. In order to exert an antiviral effect, nucleoside analogues such as ACV and DHPG first require activation to a triphosphate derivative. In the case of acyclovir, a virus-specified thymidine kinase (TK) is responsible for conversion of ACV to ACV-monophosphate.Subsequent phosphorylation is carried out by cellular kinases, and the resulting triphosphate derivative acts by inhibition of viral DNA synthesis through interaction with viral DNA polymerase. ACV has significantly diminished activity against viruses that lack thymidine kinase, such as CMV and TK-deficient strains of HSV.The related acyclic derivative ganciclovir ( 2 , DHPG)Because the efficiency of the phosphorylation process is an important factor in determining the antiviral activity of these 145 Copyright 0 1990 by Marcel Dekker, Inc. Downloaded by [New York University] at 09:44 30 May 2015 BRONSON ET AL. 7 46nucleoside analogues, there has been considerable interest in the synthesis of acyclic analogues of nucleoside phosphates (nucleotides) as well. acyclic nucleotide analogues which possess broad-spectrum antiviral activity. 7'8 of a stable phosphonylmethyl ether group [RO-CH2-P(0)(OH)2] in place of the labile phosphate moiety. serves an important role in conferring electronic properties similar to those of the phosphate to the phosphonate group. In addition, these compounds bear an alkyl linkage to the heterocyclic base in place of the usual glycosylic bond. evaluation of the cytosine derivative (S)-l-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (3, HPMPC), a compound which has good in vitro activity against herpes simplex viruses, '-11 and is more potent than 9,lO ACV in vivo against both HSV 1 and HSV 2 infections in mice. HPMPC is also an effective inhibitor of human cytomegalovirus in ~itro'''~ and has demonstrated greater in vivo efficacy than DHPG in a murine CMV infection model. thetic route to this highly promising antiviral agent which involves simpler isolation procedures and fewer chromatographic purifications than our original route, In 1986, De Clercq and Holy introduced a novel class of [4][5][6] Members of this family are characterized by the presenceThe oxygen atom f 3 to the phosphorous We have been interested inIn this paper, we report a new syn-15 and is amenable to scale-up. I 3 , HPNPC 1, R = H ( R C ...

Synthesis of Substituted 5′‐Aminoadenosine Derivatives and Evaluation of Their Inhibitory Potential toward CD73

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Lead optimization and biological evaluation of fragment-based cN-II inhibitors

“…(scheme 2 for N-1-imidazole substitution) was performed employing diethyl ptoluenesulfonyloxymethylphosphonate as required alkylating reagent [28]. Enzymatic studies.…”

“…Diethyl p-toluenesulfonyloxymethylphosphonate [28], compounds 1a-b, [43], 2a-b [44], 3 [45] and 4 [46] were prepared according to previously published procedures. (1-4).…”

Synthesis of Phosphonoglycine Backbone Units for the Development of Phosphono Peptide Nucleic Acids

“…The required alkylating reagents 33a [41] (RЈ = SO 2 C 6 H 4 CH 3 ) and 33b [42] (RЈ = SO 2 CF 3 ) were prepared according to literature procedures. The reaction of 33a with primary amines 22 and 26 gave phosphonomethylamines 34 and 35 in moderate yields (ca.…”