Relation of Metal-Binding Property and Selective Toxicity of 8-Hydroxyquinoline Derived Mannich Bases Targeting Multidrug Resistant Cancer Cells

Abstract

Resistance to chemotherapeutic agents is a major obstacle in cancer treatment. A recently proposed strategy is to target the collateral sensitivity of multidrug resistant (MDR) cancer. Paradoxically, the toxicity of certain metal chelating agents is increased, rather than decreased, by the function of P-glycoprotein (Pgp), which is known to confer resistance by effluxing chemotherapeutic compounds from cancer cells. We have recently characterized and compared the solution’s chemical properties including ligand protonation and the metal binding properties of a set of structurally related 8-hydroxyquinoline derived Mannich bases. Here we characterize the impact of the solution stability and redox activity of their iron(III) and copper(II) complexes on MDR-selective toxicity. Our results show that the MDR-selective anticancer activity of the studied 8-hydroxyquinoline derived Mannich bases is associated with the iron deprivation of MDR cells and the preferential formation of redox-active copper(II) complexes, which undergo intracellular redox-cycling to induce oxidative stress.

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

“…Functionalization of the 8-hydroxyquinoline (8-HQ) scaffold of CQ can significantly enhance the anticancer properties. CQ analogues, such as compounds 2 and 3 ( Figure 7 ) have exhibited a wide range of improvement (1.5–26-fold) in activity against various cancer cell lines, which was further potentiated by the addition of CuCl 2 [ 213 , 216 ]. The screening of focused library of 8-HQ derivatives demonstrated the importance of 8-HQ backbone for selectively targeting multidrug-resistant (MDR) cancer cells [ 217 ].…”

8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes: Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules

“…Among the bioactive ligands, 8-hydroxyquinoline (HQ) and its derivatives are extensively studied [7][8][9][10]. The HQ scaffold is used as a privileged structure due to its broad range of pharmacological properties [10][11][12][13][14][15][16][17][18][19], which are often related to the ability to coordinate to endogenous metal ions such as Fe(II/III), Cu(II) and Zn(II) [10,[13][14][15][16]. Numerous cytotoxic complexes of HQ ligands formed with rare earth metal ions [20], Pd(II) [21] or Pt(II) [22] are also reported.…”

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

“… Correlation of toxicity displayed as pIC 50 values obtained in MDR MES-SA/Dx5 (A, C, filled symbols) and parental MES-SA cells (B, D, open symbols) with p K a values of the hydroxyl group (A, B) and the quinolinium nitrogen (C, D). Data are shown for compounds 3 (gray diamond), 8 (gray triangle), 12 (gray circle), and Q-4 (gray squares), as determined previously, 50 as well as from derivatives 13 , 59 29 , 15 De-Cl-Q-4 , 15 and for 9 , 13 , 14 , 18 , 19 , 20 , 24 , 38 , 47 , 51 , 55 , 57 , 79 (black squares, described here). Representative spectra of the differently protonated species of compounds 38 and 9 are shown in Figure S1 .…”

“… 21 , 45 , 46 Whereas MDR-selective compounds identified by the pharmacogenomic approach are relatively diverse, an enrichment of metal chelators such as isatin-β-thiosemicarbazones 46 and 8-hydroxyquinoline-derived Mannich bases was observed, suggesting that complex formation with endogenous metal ions could be key to the cytotoxicity of at least a subset of the MDR-selective compounds. 15 , 21 , 22 , 42 , 46 In particular, the abundance of the 8-hydroxyquinoline scaffold is striking, as represented by the 7-diethylaminomethyl derivative NSC693872 ( 1 ), the 7-pyrrolidin-1-yl-methyl derivative NSC693871 ( 2 ), 46 and the 7-piperidin-1-yl-methyl derivative NSC57969 ( 3 ) 21 ( Table 1 ). Earlier work has established key features linked to the P -gp-potentiated activity of isatin-β-thiosemicarbazones.…”