Abstract
HIV-1 integrase catalyzes terminal cleavage at the 3′ end of the proviral DNA, removing a pair of bases and causing strand transfer by joining the 3′ end to 5′-phosphates in the target DNA. Several aryl 1,3-diketo acids that can inhibit the strand transfer reaction of HIV-1 IN have been identified. Here we synthesized a new series of compounds with a chromone or chromanone ring as conformationally constrained scaffolds of 1,3-diketo acids, and then tested their ability to inhibit HIV-1 IN-mediated strand transfer. All compounds moderately inhibited HIV-1 IN activity, indicating that the conformational restriction of one keto group into a chromone or chromanone ring decreases inhibition of the HIV-1 IN strand transfer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Appleton, R. A., Bantick, J. R., Chamberlain, T. R., Hardern, D. N., Lee, T. B., and Pratt, A. D., Antagonists of slow reacting substance of anaphylaxis. Synthesis of a series of chromone-2-carboxylic acids. J. Med. Chem., 20, 371–379 (1977).
Barreca, M. L., Ferro, S., Rao, A., De Luca, L., Zappalà, M., Monforte, A.-M., Debyser, Z., Witvrouw, M., and Chimirri, A., Pharmacophore-based design of HIV-1 integrase strand-transfer inhibitors. J. Med. Chem. 48, 7084–7088 (2005).
Barre-Sinoussi, F., Chermann, J. C., Rey, F., Nugeyre, M. T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vezinet-Brun, F., Rouzioux, C., Rozenbaum, W., and Montagnier, L., Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).
Brown, P. O., Integration of retroviral DNA. Curr. Top. Microbiol. Immunol., 157, 19–48 (1990).
Cohen, N., Bizzarro, F. T., May, W. P., Toth, K., Lee, F. K., Heslin, P. H., Holland, G. W., Kwoh, S. C., Franco, L. S., Simko, B. A., and Yagaloff, K. A., Benzenepropanoic acids containing chromanone or naphthalenone moieties are potent and orally active leukotriene B4 antagonists. Bioorg. Med. Chem. Lett., 4, 2883–2888 (1994).
Engelman, A., Englund, G., Orenstein, J. M., Martin, M. A., and Craigie, R., Multiple effects of mutations in human immuno-deficiency virus type 1 integrase on viral replication. J. Virol., 69, 2729–2736 (1995).
Foehlisch, B., New chromone synthesis. Chemische Berichte, 104, 348–349 (1971).
Grobler, J. A., Stillmock, K., Hu, B., Witmer, M., Felock, P., Espeseth, A. S., Wolfe, A., Egbertson, M., Bourgeois, M., Melamed, J., Wai, J. S., Young, S., Vacca, J., and Hazuda, D. J., Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. U.S.A., 99, 6661–6666 (2002).
Hazuda, D. J., Felock, P., Witmer, M., Wolfe, A., Stillmock, K., Grobler, J. A., Espeseth, A., Gabryelski, L., Schleif, W., Blau, C., and Miller, M. D., Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science, 287, 646–650 (2000).
Kang, J.-H., Kim, S. Y., Lee, J., Marquez, V. E., Lewin, N. E., Pearce, L. V., and Blumberg, P. M., Macrocyclic diacylglycerol-bis-lactones as conformationally constrained analogues of diacylglycerol-lactones. Interactions with protein kinase C, J. Med. Chem., 47, 4000–4007 (2004).
Lee, S. U., Park, J. H., Kwon, T. H., Yoo, Y. J., Lee, J. Y., Shin, C.-G., Yoo, K. H., and Lee, Y. S., Synthesis and HIV-1 integrase inhibitory activities of 4-hydroxy-5-azacoumarin 3-carboxamides. Bull. Korean Chem. Soc., 28, 1510–1514 (2007).
Pais, G. C. G., Zhang, X., Marchand, C., Neamati, N., Cowansage, K., Svarovskaia, E. S., Pathak, V. K., Tang, Y., Nicklaus, M., Pommier, Y., and Burke, T. R., Jr. Structure activity of 3-aryl-1,3-diketo-containing compounds as HIV-1 integrase inhibitors. J. Med. Chem., 45, 3184–3194 (2002).
Pommier, Y., Neamati, N., Inhibitors of human immuno-deficiency virus integrase. Adv. Virus Res., 52, 427–458 (1999).
Tanada, Y. and Mori, K., Synthesis and absolute configuration of (-)-neuchromenin, a neurotrophic metabolite of Eupenicillium javanicum var. meloforme, and its enantiomer. Eur. J. Org. Chem. 1963 (2001).
Wai, J. S., Egbertson, M. S., Payne, L. S., Fisher, T. E., Embrey, M. W., Tran, L. O., Melamed, J. Y., Langford, H. M., Guare, J. P., Jr., Zhuang, L., Grey, V. E., Vacca, J. P., Holloway, M. K., Naylor-Olsen, A. M., Hazuda, D. J., Felock, P. J., Wolfe, A. L., Stillmock, K. A., Schleif, W. A., Gabryelski, L. J., and Young, S. D., 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. J. Med. Chem., 43, 4923–4926 (2000).
Zhang, X., Neamati, N., Lee, Y. K., Orr, A., Brown, R. D., Whitaker, N., Pommier, Y., and Burke, T. R. Jr., Arylisothiocyanate-containing esters of caffeic acid designed as affinity ligands for HIV-1 integrase. Bioorg. Med. Chem., 9, 1649–1657 (2001).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Park, J.H., Lee, S.U., Kim, S.H. et al. Chromone and chromanone derivatives as strand transfer inhibitors of HIV-1 integrase. Arch. Pharm. Res. 31, 1–5 (2008). https://doi.org/10.1007/s12272-008-1111-z
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-008-1111-z