Structure-Activity Relationships of 8-Hydroxyquinoline-Derived Mannich Bases with Tertiary Amines Targeting Multidrug-Resistant Cancer

  • J Med Chem. 2022 Jun 9;65(11):7729-7745. doi: 10.1021/acs.jmedchem.2c00076.
Veronika F S Pape  1  2 ,  Roberta Palkó  3 ,  Szilárd Tóth  1 ,  Miklós J Szabó  4 ,  Judit Sessler  1 ,  György Dormán  5 ,  Éva A Enyedy  6 ,  Tibor Soós  3 ,  István Szatmári  7 ,  Gergely Szakács  1  8
Affiliations
  • 1. Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
  • 2. Department of Physiology, Semmelweis University, Faculty of Medicine, Tűzoltó utca 37-47, H-1094 Budapest, Hungary.
  • 3. Institute of Organic Chemistry, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.
  • 4. ChemAxon Ltd., Váci út 133, H-1138 Budapest, Hungary.
  • 5. TargetEx Ltd., Madách Imre u 31/2., H-2120 Dunakeszi, Hungary.
  • 6. Department of Inorganic and Analytical Chemistry, MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
  • 7. Institute of Pharmaceutical Chemistry and Stereochemistry Research Group of Hungarian Academy of Sciences, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary.
  • 8. Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
PMID: 35613553 DOI: 10.1021/acs.jmedchem.2c00076
Abstract

A recently proposed strategy to overcome multidrug resistance (MDR) in Cancer is to target the collateral sensitivity of otherwise resistant cells. We designed a library of 120 compounds to explore the chemical space around previously identified 8-hydroxyquinoline-derived Mannich Bases with robust MDR-selective toxicity. We included compounds to study the effect of halogen and alkoxymethyl substitutions in R5 in combination with different Mannich Bases in R7, a shift of the Mannich base from R7 to R5, as well as the introduction of an aromatic moiety. Cytotoxicity tests performed on a panel of parental and MDR cells highlight a strong influence of experimentally determined pKa values of the donor atom moieties, indicating that protonation and metal chelation are important factors modulating the MDR-selective Anticancer activity of the studied compounds. Our results identify structural requirements increasing MDR-selective Anticancer activity, providing guidelines for the development of more effective Anticancer chelators targeting MDR Cancer.