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

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.