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Antimicrobial Agents and Chemotherapy, June 1999, p. 1487-1490, Vol. 43, No. 6
0066-4804/99/$04.00+0

In Vitro Anti-Human Immunodeficiency Virus Activities of Z- and E-Methylenecyclopropane Nucleoside Analogues and Their Phosphoro-L-Alaninate Diesters

Hiroyuki Uchida,1 Eiichi N. Kodama,1 Kazuhisa Yoshimura,1 Yosuke Maeda,1 Pope Kosalaraksa,1 Victor Maroun,1 Yao-Ling Qiu,2 Jiri Zemlicka,2 and Hiroaki Mitsuya1,3,*

The Experimental Retrovirology Section, Department of Developmental Therapeutics, Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208921; Department of Chemistry, Experimental and Clinical Chemotherapy Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-13792; and Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860, Japan3

Received 3 November 1998/Returned for modification 3 February 1999/Accepted 31 March 1999

Nucleoside analogues with a Z- or an E-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-L-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 µM, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.

* Corresponding author. Mailing address: Experimental Retrovirology Section, Medicine Branch, National Cancer Institute, Bldg. 10, Room 5A11, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-9238. Fax: (301) 402-0709. E-mail: hmitsuya{at}helix.nih.gov.

Antimicrobial Agents and Chemotherapy, June 1999, p. 1487-1490, Vol. 43, No. 6
0066-4804/99/$04.00+0


This article has been cited by other articles:

  • Rybak, R. J., Hartline, C. B., Qiu, Y.-L., Zemlicka, J., Harden, E., Marshall, G., Sommadossi, J.-P., Kern, E. R. (2000). In Vitro Activities of Methylenecyclopropane Analogues of Nucleosides and Their Phosphoralaninate Prodrugs against Cytomegalovirus and Other Herpesvirus Infections. Antimicrob. Agents Chemother. 44: 1506-1511 [Abstract] [Full Text]  
  • Yoshimura, K., Feldman, R., Kodama, E., Kavlick, M. F., Qiu, Y.-L., Zemlicka, J., Mitsuya, H. (1999). In Vitro Induction of Human Immunodeficiency Virus Type 1 Variants Resistant to Phosphoralaninate Prodrugs of Z-Methylenecyclopropane Nucleoside Analogues. Antimicrob. Agents Chemother. 43: 2479-2483 [Abstract] [Full Text]  


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