Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] is an excellent target for the development of new drugs to treat parasitic and bacterial infections as well as MYC-dependent triple-negative breast cancer. Inhibitors include compounds that mimic the transition state of the catalytic reaction and analogs of the two products of the reaction, the nucleoside monophosphates and pyrophosphate. One type of chemistry explored here is the design of purine-based C1'-branched acyclic nucleoside phosphonates bearing diverse structural attachments (secondary linkers) on the C1' atom. Compounds where this secondary linker has either a terminal phosphonate or a hydroxyl group are submicromolar to single-digit micromolar inhibitors of human hypoxanthine-guanine phosphoribosyltransferase and Plasmodium falciparum HGXPRT. The lowest Ki values for two of these inhibitors are 0.7 µM for the human enzyme and 0.4 µM for the parasite enzyme. The Ki values of the prepared derivatives, however, cover a wide range and depend on the chemical structure of the attachment at the C1' atom. A phosphonodiamidate prodrug of one of the compounds has an IC50 of 4.3 µM against a drug-sensitive strain of Plasmodium falciparum grown in human erythrocytes, showing in vitro activity and the merit of these new inhibitors as potential drug leads.

Department of Drug Evaluation Australian Defence Force Malaria and Infectious Disease Institute Enoggera Brisbane Queensland 4051 Australia

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 160 00 Prague 6 Czech Republic

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane 4072 Australia

Zobrazit více v PubMed

Booden T., Hull R. W., Exp. Parasitol. 1973, 34, 220. PubMed

Downie M. J., Kirk K., Mamoun C. B., Eukaryot Cell. 2008, 7, 1231. PubMed PMC

Ward P., Equinet L., Packer J., Doerig C., BMC Genomics 2004, 5, 79. PubMed PMC

Cassera M. B., Hazleton K. Z., Riegelhaupt P. M., Merino E. F., Luo M., Akbas M. H., Schramm V. L., J. Biol. Chem. 2008, 283, 32889. PubMed PMC

Cheviet T., Lefebvre‐Tournier I., Wein S., Peyrottes S., J. Med. Chem. 2019, 62, 8365. PubMed

Queen S. A., Jagt D. V., Reyes P., Mol. Biochem. Parasitol. 1988, 30, 123. PubMed

Keough D. T., Ng A. L., Winzor D. J., Emmerson B. T., de Jersey J., Mol. Biochem. Parasitol. 1999, 98, 29. PubMed

Keough D. T., Skinner‐Adams T., Jones M. K., Ng A. L., Brereton I. M., Guddat L. W., de Jersey J., J. Med. Chem. 2006, 49, 7479. PubMed

Hazleton K. Z., Ho M. C., Cassera M. B., Clinch K., Crump D. R., E. F. M. I. Rosario Jr., Almo S. C., Tyler P. C., Schramm V. L., Chem. Biol. 2012, 19, 721. PubMed PMC

Keough D. T., Hocková D., Holý A., Naesens L. M., Skinner‐Adams T. S., Jersey J., Guddat L. W., J. Med. Chem. 2009, 52, 4391. PubMed

Keough D. T., Rejman D., Pohl R., Zborníková E., Hocková D., Croll T., Edstein M. D., Birrell G. W., Chavchich M., Naesens L. M. J., Pierens G. K., Brereton I. M., Guddat L. W., ACS Chem. Biol. 2018, 13, 82. PubMed

Keough D. T., Petrová M., King G., Kratochvíl M., Pohl R., Doleželová E., Zíková A., Guddat L. W., Rejman D., J. Med. Chem. 2024, 67, 7158. PubMed PMC

Shi W., Li C. M., Tyler P. C., Furneaux R. H., Grubmeyer C., Schramm V. L., Almo S. C., Nat. Struct. Biol. 1999, 6, 588. PubMed

Shi W., Li C. M., Tyler P. C., Furneaux R. H., Cahill S. M., Girvin M. E., Grubmeyer C., Schramm V. L., Almo S. C., Biochemistry 1999, 38, 9872. PubMed

Meena J. K., Wang J. H., Neill N. J., Keough D., Putluri N., Katsonis P., Koire A. M., Lee H., Bowling E. A., Tyagi S., Orellana M., Dominguez‐Vidana R., Li H., Eagle K., Danan C., Chung H. C., Yang A. D., Wu W., Kurley S. J., M. B., Ho J. R. Z., Olson C. M., Meerbrey K. L., Lichtarge O., Sreekumar A., Dacso C. C., Guddat L. W., Rejman D., Hocková D., Janeba Z., Simon L. M., Lin C. Y., Pillon M. C., Westbrook T. F., Cancer Discov. 2024, 14, 1699. PubMed PMC

Li C. M., Tyler P. C., Furneaux R. H., Kicska G., Xu Y., Grubmeyer C., Girvin M. E., Schramm V. L., Nat. Struct. Biol. 1999, 6, 582. PubMed

Keough D. T., Špaček P., Hocková D., Tichý T., Vrbková S., Slavětínská L., Janeba Z., Naesens L., Edstein M. D., Chavchich M., Wang T. H., de Jersey J., Guddat L. W., J. Med. Chem. 2013, 56, 2513. PubMed

Špaček P., Keough D. T., Chavchich M., Dračínský M., Janeba Z., Naesens L., Edstein M. D., Guddat L. W., Hocková D., J. Med. Chem. 2017, 60, 7539. PubMed

Hocková D., Keough D. T., Janeba Z., Wang T. H., de Jersey J., Guddat L. W., J. Med. Chem. 2012, 55, 6209. PubMed

Keough D. T., Hocková D., Janeba Z., Wang T. H., Naesens L., Edstein M. D., Chavchich M., Guddat L. W., J. Med. Chem. 2015, 58, 827. PubMed

Eng W. S., Hocková D., Špaček P., Janeba Z., West N. P., Woods K., Naesens L. M., Keough D. T., W.Guddat L., J. Med. Chem. 2015, 58, 4822. PubMed

Frydrych J., Skácel J., Šmídková M., Mertlíková‐Kaiserová H., Dračínský M., Gnanasekaran R., Lepšík M., Soto‐Velasquez M., Watts V. J., Janeba Z., ChemMedChem 2018, 13, 199. PubMed

Frydrych J., Slavětínská L. P.štová, Dračínský M., Janeba Z., Molecules 2020, 25, 4307. PubMed PMC

Kalčic F., Dračínský M., Janeba Z., Z. Org. Biomol. Chem. 2021, 19, 6958. PubMed

Kalčic F., Frydrych J., Doleželová E., Slapničková M., Pachl P., Slavětínská L. P.štová, Dračínský M., Hocková D., Zíková A., Janeba Z., Eur. J. Med. Chem. 2021, 225, 113798. PubMed

Keough D. T., Brereton I. M., de Jersey J., Guddat L. W., J. Mol. Biol. 2025, 351, 170. PubMed

Balendiran G. K., Molina J. A., Xu Y., Torres‐Martinez J., Stevens R., Focia P. J., Eakin A. E., Sacchettini J. C., Craig S. P., Protein Sci. 1999, 8, 1023. PubMed PMC

Eads J. C., Scapin G., Xu Y., Grubmeyer C., Sacchettini J. C., Cell 1994, 78, 325. PubMed

Klejch T., Keough D. T., King G., Doleželová E., Česnek M., Buděšínský M., Zíková A., Janeba Z., Guddat L. W., Hockova D., J. Med. Chem. 2022, 65, 4030. PubMed

O’Boyle N. M., Banck M., James C. A., Morley C., Vandermeersch T., Hutchison G. R., J Cheminform. 2011, 3, 33. PubMed PMC

Jones G., Willett P., Glen R. C., Leach A. R., Taylor R., J. Mol Biol. 1997, 267, 727. PubMed

Kaiser M. M., Hocková D., Wang T. H., Dračínský M., Poštová‐Slavětínská L., Procházková E., Edstein M. D., Chavchich M., Keough D. T., Guddat L. W., Janeba Z., ChemMedChem 2015, 10, 1707. PubMed

Trager W., Jensen J. B., Science 1976, 193, 673. PubMed

Lambros C., Vanderberg J. P., J. Parasitol. 1979, 65, 418. PubMed