Synthesis and antiviral activity of the nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine.
The acyclic nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl] cytosine (2, HPMPC) was prepared on a multigram scale in 18% overall yield starting from (R)-2,3-O-isopropylideneglycerol. The key step in the nine-step synthetic route is coupling of cytosine with the side-chain derivative 8 which bears a protected phosphonylmethyl ether group. In vitro data showed that HPMPC has good activity against herpes simplex virus types 1 and 2, although it was 10-fold less potent than acyclovir [AVC, 9-[(2-hydroxyethoxy)methyl]guanine]. By comparison, HPMPC exhibited greater activity than ACV against a thymidine kinase deficient strain of HSV 1 and was more potent than ganciclovir [DHPG, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine] against human cytomegalovirus. In vivo, HPMPC showed exceptional potency against HSV 1 systemic infection in mice, having an ED50 of 0.1 mg/kg per day (ip) compared with 50 mg/kg per day for ACV. HPMPC was also more efficacious than ACV in the topical treatment of HSV 1 induced cutaneous lesions in guinea pigs.
Bronson
J J
JJ
Bristol-Myers Pharmaceutical Research and Development Division, Wallingford, Connecticut 06492-7660.
Ghazzouli
I
I
Hitchcock
M J
MJ
Webb
R R
RR
Martin
J C
JC
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003597:Cytosine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects; D014709:Vero Cells
D000998:Antiviral Agents; D003597:Cytosine Nucleotides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir