Russian Chemical Bulletin

, Volume 68, Issue 1, pp 168–173 | Cite as

Structural optimization of adaptaquin, a HIF prolyl hydroxylase inhibitor

  • A. A. PoloznikovEmail author
  • A. Yu. Khristichenko
  • N. A. Smirnova
  • D. M. Hushpulian
  • I. N. Gaisina
  • A. I. Osipyants
  • V. I. Tishkov
  • I. G. Gazaryan
Full Articles


The structural optimization of adaptaquin, viz., 7-(4-chlorophenyl)[(3-hydroxypyridin-2-yl)amino]methylquinolin-8-ol, a HIF (hypoxia inducible factor) prolyl hydroxylase inhibitor, was carried out. This was done by cell-based screening using cell lines stably expressing a reporter construct consisting of the fusion protein of HIF oxygen-dependent domain and firefly luciferase (HIF1 ODD-luc). More than 100 structural analogs of adaptaquin were screened and the structures active in the submicromolar range were selected. The highest activity was found for analogs containing isobutyl, isopropyl, trifluoromethyl, and nitro group or halogen atom in the para-position of the benzene ring, but not a dimethylamino group or more bulky substituents. The lack of dependence on the donor-acceptor properties of substituents attests to predominance of the steric effect. The presence of methyl group in positions 3 and 5 of the pyridine ring provides additional activation. The 2-methyl group present in the hydroxyquinoline scaffold (50 compounds in the set) prevents coordination of the inhibitor in the active site and significantly reduces the activation. According to the real-time PCR results, the newly improved adaptaquin analog induces HIF target genes 15-times more efficiently than the FG-4592 inhibitor developed by Fibrogen.

Key words

hydroxyquinoline structure–activity relationship reporter assay hypoxia-inducible factor (HIV) inhibitor 


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  1. 1.
    K. Franke, M. Gassmann, B. Wielockx, Blood, 2013, 122, 1122.CrossRefGoogle Scholar
  2. 2.
    A. A. Joharapurkar, V. B. Pandya, V. J. Patel, R. C. Desai, M. R. Jain, J. Med. Chem., 2018, 61, 6964.CrossRefGoogle Scholar
  3. 3.
    M. H. Rabinowitz, J. Med. Chem., 2013, 56, 9369.CrossRefGoogle Scholar
  4. 4.
    D. Kular, I. C. Macdougall, Pediatr. Nephrol., 2018, DOI 10.1007/s00467-017-3849-3.Google Scholar
  5. 5.
    M. Ivan, W. G. Kaelin, Mol. Cell, 2017, 66, 772.CrossRefGoogle Scholar
  6. 6.
    V. Cernaro, G. Coppolino, L. Visconti, L. Rivoli, A. Lacquaniti, D. Santoro, A. Buemi, S. Loddo, M. Buemi, Med. Res. Rev., 2018, DOI 10.1002/med.21527.Google Scholar
  7. 7.
    N. A. Smirnova, D. M. Hushpulian, R. E. Speer, I. N. Gaisina, R. R. Ratan, I. G. Gazaryan, Biochemistry (Moscow), 2012, 77, 1108.CrossRefGoogle Scholar
  8. 8.
    S. S. Karuppagounder, I. Alim, S. J. Khim, M. W. Bourassa, S. F. Sleiman, R. John, C. C. Thinnes, T.-L. Yeh, M. Demetriades, S. Neitemeier, D. Cruz, I. Gazaryan, D. W. Killilea, L. Morgenstern, G. Xi, R. F. Keep, T. Schallert, R. V. Tappero, J. Zhong, S. Cho, F. R. Maxfield, T. R. Holman, C. Culmsee, G.-H. Fong, Y. Su, G. Ming, H. Song, J. W. Cave, C. J. Schofield, F. Colbourne, G. Coppola, R. R. Ratan, Sci. Transl. Med., 2016, 8, 328ra29.CrossRefGoogle Scholar
  9. 9.
    N. A. Smirnova, I. Rakhman, N. Moroz, M. Basso, J. Payappilly, S. Kazakov, F. Hernandez-Guzman, I. N. Gaisina, A. P. Kozikowski, R. R. Ratan, I. G. Gazaryan, Chem. Biol., 2010, 17, 380.CrossRefGoogle Scholar
  10. 10.
    I. N. Gaisina, A. Yu. Khristichenko, A. M. Gaisin, N. A. Smirnova, I. G. Gazaryan, A. A. Poloznikov, Russ. Chem. Bull., 2018, 67, 2320.CrossRefGoogle Scholar
  11. 11.
    A. I. Osipyants, A. A. Poloznikov, N. A. Smirnova, D. M. Hushpulian, A. Y. Khristichenko, T. A. Chubar, A. A. Zakhariants, M. Ahuja, I. N. Gaisina, B. Thomas, A. M. Brown, I. G. Gazaryan, V. I. Tishkov, Biochimie, 2018, 147, 46.CrossRefGoogle Scholar
  12. 12.
    M. Obach, A. Navarro-Sabaté, J. Caro, X. Kong, J. Duran, M. Gómez, J. C. Perales, F. Ventura, J. L. Rosa, R. Bartrons, J. Biol. Chem., 2004, 279, 53562.CrossRefGoogle Scholar
  13. 13.
    H. Zhang, C. Lu, M. Fang, W. Yan, M. Chen, Y. Ji, S. He, T. Liu, T. Chen, J. Xiao, Biochem. Biophys. Res. Commun., 2016, 476, 146.CrossRefGoogle Scholar
  14. 14.
    A. Leiherer, K. Geiger, A. Muendlein, H. Drexel, Mol. Cell. Endocrinol., 2014, 383, 21.CrossRefGoogle Scholar
  15. 15.
    X.-G. Cui, Z.-T. Han, S.-H. He, X. Wu, T.-R. Chen, C.-H. Shao, D.-L. Chen, N. Su, Y.-M. Chen, T. Wang, J. Wang, D.-W. Song, W.-J. Yan, X.-H. Yang, T. Liu, H.-F. Wei, J. Xiao, Oncotarget, 2017, 8, 24840.Google Scholar
  16. 16.
    D. Ciarlillo, C. Celeste, P. Carmeliet, D. Boerboom, C. Theoret, PLoS One, 2017, 12, e0180586.Google Scholar
  17. 17.
    H. Zhao, Y. Wu, Y. Chen, H. Liu, Int. J. Clin. Oncol., 2015, 20, 1233.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2019

Authors and Affiliations

  • A. A. Poloznikov
    • 1
    • 2
    Email author
  • A. Yu. Khristichenko
    • 1
  • N. A. Smirnova
    • 1
  • D. M. Hushpulian
    • 1
  • I. N. Gaisina
    • 3
  • A. I. Osipyants
    • 1
  • V. I. Tishkov
    • 4
    • 5
    • 6
  • I. G. Gazaryan
    • 1
    • 4
  1. 1.Dmitry Rogachev National Medical Research Center for Pediatric Hematology, Oncology, and ImmunologyMoscowRussian Federation
  2. 2.National Medical Research Radiological CenterMinistry of Health of the Russian FederationObninskRussian Federation
  3. 3.Department of Medicinal Chemistry and PharmacognosyUniversity of Illinois at ChicagoChicagoUSA
  4. 4.Department of ChemistryM. V. Lomonosov Moscow State UniversityMoscowRussian Federation
  5. 5.Innovations and High Technologies MSU Ltd.MoscowRussian Federation
  6. 6.A. N. Bach Institute of Biochemistry, Russian Academy of SciencesFederal Research Center “Fundamentals of Biotechnology”MoscowRussian Federation

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