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

Abstract

Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C5Me5) and Ru(η6-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity.

Organometallic Ru(ii), Rh(iii) and Re(i) complexes of sterane-based bidentate ligands: synthesis, solution speciation, interaction with biomolecules and anticancer activity

“…Therefore, the lipophilicity at different concentrations of chloride ions was assessed in a similar manner to that described in our previous reports, taking into account the diverse chloride ion concentrations found in the biofluids. [49][50][51] For this purpose, n-octanol/buffered aqueous solution partitioning was performed at pH = 7.40. The determined log D pH=7.40 values are depicted in Fig.…”

Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction

“…There are derivatives that act by inhibiting DNA biosynthesis [32,44], MetAP2 [45], JMJD2C [46], and Rcel [47]. MDR-targeting agents have been studied as well [48,49], while in some derivatives, the metal-binding property has been utilised to enhance the antiproliferative activity [50][51][52][53]. The effects on the MAPK pathway [54], the caspase-dependent apoptotic pathway [55,56] and survivin [57,58] have also been examined, while some 5-nitro compounds were associated with inhibition of cathepsin B [59][60][61][62].…”

Implicatons of Metal Complexes in Biology and Medicine the System Cadmium (II)/ Iron (II)/ Zinc (II)-Hydroxyproline

“…Me 5 ) and ruthenium (n 6 -p-cymene) complexes with excellent aqueous solubility were developed, characterized against sensitive and multiple drug resistance cells(Pivarcsik et al, 2023). A complex of zinc and carnosine called zinc -L-carnosine has been extensively used in tumor adjuvant therapy(Tang et al, 2022).…”