Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 Oct;37(10):2247–2250. doi: 10.1128/aac.37.10.2247

Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates.

R V Srinivas 1, B L Robbins 1, M C Connelly 1, Y F Gong 1, N Bischofberger 1, A Fridland 1
PMCID: PMC192261  PMID: 8257154

Abstract

Bis(pivaloyloxymethyl) [bis(pom)] derivatives of various acyclic nucleoside phosphonates--9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-(2-phosphonylmethoxypropyl)adenine (PMPA), and 9-(2-phosphonylmethoxypropyl)diaminopurine (PMPDAP)--were found to exhibit 9- to 23-fold greater antiviral activity than their corresponding unmodified compounds. The cytotoxicity of the bis(pom) analogs was also increased by various degrees, thus altering the therapeutic indexes of these compounds. Metabolic studies using [3H]bis(pom)PMEA and [3H]PMEA as model compounds suggested a > 100-fold increase in the cellular uptake of the bis(pom) derivative and formation of active diphosphorylated metabolite. However, the bis(pom) derivatives were chemically unstable and highly susceptible to serum-mediated hydrolysis, factors which limit their potential utility for intracellular drug delivery.

Full text

PDF
2247

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahluwalia G., Cooney D. A., Bondoc L. L., Jr, Currens M. J., Ford H., Johns D. G., Mitsuya H., Fridland A. Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the antiviral nucleoside 2' ,3'-dideoxyguanosine. Biochem Biophys Res Commun. 1990 Sep 28;171(3):1297–1303. doi: 10.1016/0006-291x(90)90827-a. [DOI] [PubMed] [Google Scholar]
  2. Bondoc L. L., Jr, Shannon W. M., Secrist J. A., 3rd, Vince R., Fridland A. Metabolism of the carbocyclic nucleoside analogue carbovir, an inhibitor of human immunodeficiency virus, in human lymphoid cells. Biochemistry. 1990 Oct 23;29(42):9839–9843. doi: 10.1021/bi00494a013. [DOI] [PubMed] [Google Scholar]
  3. Cerny J., Foster S. A., Cheng Y. C. Cell-protecting effect against herpes simplex virus-1 and cellular metabolism of 9-(2-phosphonylmethoxyethyl)adenine in HeLa S3 cells. Mol Pharmacol. 1992 Sep;42(3):537–544. [PubMed] [Google Scholar]
  4. De Clercq E. Broad-spectrum anti-DNA virus and anti-retrovirus activity of phosphonylmethoxyalkylpurines and -pyrimidines. Biochem Pharmacol. 1991 Aug 8;42(5):963–972. doi: 10.1016/0006-2952(91)90276-b. [DOI] [PubMed] [Google Scholar]
  5. Freed J. J., Farquhar D., Hampton A. Evidence for acyloxymethyl esters of pyrimidine 5'-deoxyribonucleotides as extracellular sources of active 5'-deoxyribonucleotides in cultured cells. Biochem Pharmacol. 1989 Oct 1;38(19):3193–3198. doi: 10.1016/0006-2952(89)90613-8. [DOI] [PubMed] [Google Scholar]
  6. Johnson M. A., Ahluwalia G., Connelly M. C., Cooney D. A., Broder S., Johns D. G., Fridland A. Metabolic pathways for the activation of the antiretroviral agent 2',3'-dideoxyadenosine in human lymphoid cells. J Biol Chem. 1988 Oct 25;263(30):15354–15357. [PubMed] [Google Scholar]
  7. Melegh B. Carnitine supplementation in pivampicillin treatment. Lancet. 1989 Nov 4;2(8671):1096–1096. doi: 10.1016/s0140-6736(89)91104-5. [DOI] [PubMed] [Google Scholar]
  8. Palú G., Stefanelli S., Rassu M., Parolin C., Balzarini J., De Clercq E. Cellular uptake of phosphonylmethoxyalkylpurine derivatives. Antiviral Res. 1991 Jul;16(1):115–119. doi: 10.1016/0166-3542(91)90063-w. [DOI] [PubMed] [Google Scholar]
  9. Sastry J. K., Nehete P. N., Khan S., Nowak B. J., Plunkett W., Arlinghaus R. B., Farquhar D. Membrane-permeable dideoxyuridine 5'-monophosphate analogue inhibits human immunodeficiency virus infection. Mol Pharmacol. 1992 Mar;41(3):441–445. [PubMed] [Google Scholar]
  10. Starrett J. E., Jr, Tortolani D. R., Hitchcock M. J., Martin J. C., Mansuri M. M. Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine. Antiviral Res. 1992 Sep;19(3):267–273. doi: 10.1016/0166-3542(92)90084-i. [DOI] [PubMed] [Google Scholar]
  11. Weislow O. S., Kiser R., Fine D. L., Bader J., Shoemaker R. H., Boyd M. R. New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity. J Natl Cancer Inst. 1989 Apr 19;81(8):577–586. doi: 10.1093/jnci/81.8.577. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES