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

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 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.

Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells

“…Previously, we have reported 8-hydroxyquinoline derived Mannich bases possessing excellent water solubility related to their zwitterionic form [12,13]. Additionally, the CH 2 -N subunit at the seventh position on the HQ ring proved to be beneficial in terms of MDR selectivity [5,7]. We have shown that the cytotoxicity and MDR-selectivity of 8-hydroxyquinoline Mannich bases are related to their complex formation with essential metal ions [5,7,14].…”

“…A recently proposed strategy to overcome multidrug resistance is to target the collateral sensitivity of otherwise resistant cells by MDR-selective compounds. In earlier work, we designed a library containing a high number (>500) of 8-hydroxyquinoline (HQ) derivatives possessing variable MDR-selective toxicity [5][6][7]. The toxicity of MDR-selective 8-HQ derivatives is increased, rather than decreased, by P-gp [8].…”

“…Additionally, the CH 2 -N subunit at the seventh position on the HQ ring proved to be beneficial in terms of MDR selectivity [5,7]. We have shown that the cytotoxicity and MDR-selectivity of 8-hydroxyquinoline Mannich bases are related to their complex formation with essential metal ions [5,7,14]. We have characterized the acid-base properties and metal binding abilities of a series of HQs derived Mannich bases with tertiary amines [5,7,14].…”

“…We have shown that the cytotoxicity and MDR-selectivity of 8-hydroxyquinoline Mannich bases are related to their complex formation with essential metal ions [5,7,14]. We have characterized the acid-base properties and metal binding abilities of a series of HQs derived Mannich bases with tertiary amines [5,7,14]. Among others, a relationship was found between the pK a values (mainly for the OH group) and the cytotoxicity against MDR cells in the case of a library consisting of 120 derivatives [7].…”

Synthesis of Selenyl-Substituted Quinoline Derivatives via Substrate-Controlled Three-Component Domino Reactions

“…Introduction of selenium into organic molecules has recently been the subject of intense research as organoselenium compounds have found widespread applications in the field of drug discovery . Quinoline-containing organoselenium compounds have recently received considerable attention because the quinoline moiety is a well-documented privileged structure in natural products and pharmaceuticals for discovering lead compounds. Among the numerous selenyl-substituted quinoline derivatives, 3-selenoacetyl quinolines are an important class of compounds; much effort has been devoted to the preparation of this compound.…”