Isoxazole‐Derived Aroylhydrazones and Their Dinuclear Copper(II) Complexes Show Antiproliferative Activity on Breast Cancer Cells with a Potentially Alternative Mechanism Of Action

Abstract

This paper reports the design, synthesis and cytotoxicity studies of two new isoxazole‐derived aroylhydrazone ligands and their dinuclear copper(II) complexes. Compounds were fully characterized by various spectroscopic and analytical techniques. The molecular structures of four derivatives were confirmed by X‐ray crystallography. The stability of the ligands and the complexes in aqueous medium was monitored spectroscopically. Both the ligands and the complexes were shown to interact with calf thymus DNA (ct‐DNA). Additionally, structures containing a phenol pendant arm were significantly more cytotoxic than those carrying a pendant pyridine substituent, reaching sub‐micromolar IC50 values on the triple‐negative human breast cancer cell line MDA‐MB‐231. The metal chelation and transchelation ability of the compounds towards FeII, FeIII and ZnII ions was explored as a possible mechanism of action of these compounds.

Novel luminescent benzopyranothiophene- and BODIPY-derived aroylhydrazonic ligands and their dicopper(II) complexes: syntheses, antiproliferative activity and cellular uptake studies

“…Similarly, complexes derived from the BODIPYrelated ligand H3L2 can be formulated as [Cu2(H2L2)(OH2)3](ClO4)3•7H2O (3) and [Cu2(HL2)(O2CMe)(OH2)2](MeCO2)•5H2O (4). In complex 3, we propose that the terminal phenol group from H3L2 remains protonated after coordination, as reported by us for similar systems [16].…”

“…Scheme 1 Synthetic routes to ligands H3L1 and H3L2 (top), and their dicopper(II) complexes from perchlorate, 1 and 3, or acetate, 2 and 4, salts (bottom). In the case of the acetato complexes, the coordination mode of this anion was suggested on the basis of a structure-related compound previously published by our group [16].…”

“…As part of a wide research program initially aimed at the design of synthetic mimics for dinuclear metalloenzymes such as catechol oxidase, a type-3 copper enzyme, some of us introduced several new binucleating Schiff-base ligands whose dicopper(II) complexes exhibited significant nuclease activity [13,14]. More recently, we reported the synthesis of several unsymmetrical binucleating ligands comprising of an aroylhydrazone moiety and a N,N,N or N,N,O tridentate pendant arm joined together by a central 4methylphenol ring (BPMAMFF-Hz and HBPAMFF-Hz in Figure 1) and their dicopper(II) complexes [15,16]. The biological properties of the ligands and complexes were extensively studied and revealed that the complexes derived from the HBPAMFF-Hz ligands were highly cytotoxic towards the triple negative breast cancer cell line MDA-MB-231, whereas the ones containing the ligand BPMAMFF-Hz were virtually inactive (IC50 > 10 µM).…”

Exploring the Potential of Metallodrugs as Chemotherapeutics for Triple Negative Breast Cancer

“…[66] Dinuclear copper (II) compounds containing isoxazolederived aroylhydrazones displayed cytotoxicity on MDA-MB-231 (sub-micromolar range) and the interactions of these compounds with calf-thymus DNA was demonstrated. [74] More effective copper (II) compounds with dithiocarbamate ligands were reported by Dou and co-workers. [67][68][69] The addition of CuCl 2 to Disulfiram (DSF) a drug used for the treatment of alcoholism (and with antitumor and chemosensitizing activities) generates a DSF-copper complex (30 in Scheme 4) that is cytotoxic on MDA-MB-231 cells, highly selective when compared to MCF10a breast cells, and like gold (III) compound 25, inhibits the proteasomal activity in these cells before inducing apoptosis.…”

“…Auranofin, a gold(I) compound currently being studied in clinical trials for non-small cell lung and ovarian cancer, [54] and some selected gold, silver and copper compounds that have undergone preclinical TNBC studies. [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74] proteasome was the major target for the two compounds reported in MDA-MB-231 cell lines, and mice xenograft models (see Figure 2). They also observed 53 % of growth inhibition (with some animals even showing tumor shrinkage) for mice treated with a low dose (1 mg/kg per day for 27 days) with almost no systemic toxicity.…”