Solution chemical properties and anticancer potential of 8-hydroxyquinoline hydrazones and their oxidovanadium(IV) complexes

We report the synthesis and characterization of a family of benzohydrazones (Ln, n = 1–6) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing different substituents in the para position. Their oxidovanadium(IV) complexes were prepared and compounds with 1:1 and 1:2 metal-to-ligand stoichiometry were obtained. All compounds were characterized by elemental analyses and mass spectrometry as well as FTIR, UV–visible absorption, NMR (ligand precursors) and EPR (complexes) spectroscopies, and by DFT computational methods. Proton dissociation constants, lipophilicity and solubility in aqueous media were determined for all ligand precursors. Complex formation with V(IV)O was evaluated by spectrophotometry for L4 (Me-substituted) and L6 (OH-substituted) and formation constants for mono [VO(HL)]+, [VO(L)] and bis [VO(HL)2], [VO(HL)(L)]−, [VO(L)2]2− complexes were determined. EPR spectroscopy indicates the formation of [VO(HL)]+ and [VO(HL)2], with this latter being the major species at the physiological pH. Noteworthy, the EPR data suggest a different behaviour for L4 and L6, which confirm the results obtained in the solid state. The antiproliferative activity of all compounds was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. All complexes show much higher activity on A-375 (IC50 < 6.3 μM) than in A-549 cells (IC50 > 20 μM). Complex 3 (F-substituted) shows the lowest IC50 on both cell lines and lower than cisplatin (in A-375). Studies identified this compound as the one showing the highest increase in Annexin-V staining, caspase activity and induction of double stranded breaks, corroborating the cytotoxicity results. The mechanism of action of the complexes involves reactive oxygen species (ROS) induced DNA damage, and cell death by apoptosis.

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Funding Information: This work was supported by Centro de Química Estrutural, which is financed by national funds from Fundação para a Ciência e Tecnologia (FCT), projects LA/P/0056/2020, and Programa Operacional Regional de Lisboa 2020. The Portuguese NMR and Mass spectrometry IST-UL are acknowledged for the access to the equipment. This work was supported by the Portuguese-Hungarian Scientific & Technological CooperationTÉT-PT-2018-00002, ÚNKP-21-3-SZTE-455 (to V. Pósa) New National Excellence Program Ministry of Human Capacities. The support of the ‘Lendület’ Programme (ELKH, LP2019-6/2019) and the COST ActionCA18202, NECTAR-Network for Equilibria and Chemical Thermodynamics Advanced Research is also acknowledged. This work was also supported by Koç University School of Medicine (KUSOM) and the authors gratefully acknowledge use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Turkey, Presidency of Strategy and Budget. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Presidency of Strategy and Budget. G. Sciortino, V. Ugone, E. Garribba thank Fondazione di Sardegna (grant FdSGarribba2017) and Regione Autonoma della Sardegna (grant RASSR79857); G. Sciortino also thanks MICINN’ Juan de la Cierva program, FJC2019-039135-I for the financial support. Publisher Copyright: © 2022 Elsevier Inc.

Palavras-chave

8-hydroxyquinoline derivatives Anticancer Oxidovanadium(IV) complexes Schiff bases Solution stability Speciation Biochemistry Inorganic Chemistry SDG 3 - Good Health and Well-being