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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2022 May 25

PMID 35613553

Authors

Veronika F S Pape

Roberta Palko

Szilard Toth

Miklos J Szabo

Judit Sessler

Gyorgy Dorman

Eva A Enyedy

Tibor Soos

Istvan Szatmari

Gergely Szakacs

Affiliations

Soon will be listed here.

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 p 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.

Citing Articles

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