2. Academic Validation
  3. Structure-Activity Relationships of 8-Hydroxyquinoline-Derived Mannich Bases with Tertiary Amines Targeting Multidrug-Resistant Cancer

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

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.

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