Structure-Activity Relationships of 8-Hydroxyquinoline-Derived Mannich Bases with Tertiary Amines Targeting Multidrug-Resistant Cancer.
Veronika F S PapeRoberta PalkóSzilárd TóthMiklós J SzabóJudit SesslerGyörgy DormánÉva A EnyedyTibor SoósIstván SzatmáriGergely SzakacsPublished in: Journal of medicinal chemistry (2022)
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 p K a 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.
Keyphrases
- multidrug resistant
- papillary thyroid
- drug resistant
- gram negative
- acinetobacter baumannii
- induced apoptosis
- squamous cell
- klebsiella pneumoniae
- cell cycle arrest
- oxidative stress
- cancer therapy
- signaling pathway
- clinical practice
- pseudomonas aeruginosa
- cystic fibrosis
- pi k akt
- cell proliferation
- cell death
- oxide nanoparticles