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

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

Promising anticancer agents based on 8-hydroxyquinoline hydrazone copper(II) complexes

We report the synthesis and characterization of a group of benzoylhydrazones (L n ) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing distinct para substituents (R = H, Cl, F, CH 3 , OCH 3 , OH and NH 2 , for L 1-7 , respectively; in L 8 isonicotinohydrazide was used instead of benzylhydrazide). Cu(II) complexes were prepared by reaction of each benzoylhydrazone with Cu(II) acetate. All compounds were characterized by elemental analysis and mass spectrometry as well as by FTIR, UV-visible absorption, NMR or electron paramagnetic resonance spectroscopies. Complexes isolated in the solid state ( 1–8 ) are either formulated as [Cu(HL)acetate] (with L 1 and L 4 ) or as [Cu(L n )] 3 ( n = 2, 3, 5, 6, 7 and 8). Single crystal X-ray diffraction studies were done for L 5 and [Cu(L 5 )] 3 , confirming the trinuclear formulation of several complexes. Proton dissociation constants, lipophilicity and solubility were determined for all free ligands by UV-Vis spectrophotometry in 30% (v/v) DMSO/H 2 O. Formation constants were determined for [Cu(LH)], [Cu(L)] and [Cu(LH −1 )] for L = L 1 , L 5 and L 6 , and also [Cu(LH −2 )] for L = L 6 , and binding modes are proposed, [Cu(L)] predominating at physiological pH. The redox properties of complexes formed with L 1 , L 5 and L 6 are investigated by cyclic voltammetry; the formal redox potentials fall in the range of +377 to +395 mV vs. NHE. The binding of the Cu(II)-complexes to bovine serum albumin was evaluated by fluorescence spectroscopy, showing moderate-to-strong interaction and suggesting formation of a ground state complex. The interaction of L 1 , L 3 , L 5 and L 7 , and of the corresponding complexes with calf thymus DNA was evaluated by thermal denaturation. The antiproliferative activity of all compounds was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. The complexes show higher activity than the corresponding free ligand, and most complexes are more active than cisplatin. Compounds 1, 3, 5 , and 8 were selected for additional studies: while these complexes induce reactive oxygen species and double-strand breaks in both cancer cells, their ability to induce cell-death by apoptosis varies. Within the set of compounds tested, 8 emerges as the most promising one, presenting low IC 50 values, and high induction of oxidative stress and DNA damage, which eventually lead to high rates of apoptosis

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

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 UIDB/00100/2020, UIDP/00100/2020 and LA/P/0056/2020, and Programa Operacional Regional de Lisboa 2020. We also thank project PTDC/QUI-QIN/0586/2020 and N. Ribeiro acknowledges FCT for SFRH/BD/135797/2018 grant. 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. L. Maia thanks the Associate Laboratory for Green Chemistry - LAQV, which is financed by national funds from Fundação para a Ciência e a Tecnologia, MCTES (FCT/MCTES; UIDB/50006/2020 and UIDP/50006/2020). 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 UIDB/00100/2020 , UIDP/00100/2020 and LA/P/0056/2020 , and Programa Operacional Regional de Lisboa 2020 . We also thank project PTDC/QUI-QIN/0586/2020 and N. Ribeiro acknowledges FCT for SFRH/BD/135797/2018 grant. 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 Cooperation TÉT-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 Action CA18202 , 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. L. Maia thanks the Associate Laboratory for Green Chemistry - LAQV , which is financed by national funds from Fundação para a Ciência e a Tecnologia, MCTES (FCT/MCTES; UIDB/50006/2020 and UIDP/50006/2020 ). Publisher Copyright: © 2022 Elsevier Inc.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 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.publishersversionpublishe

Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance

COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe2 and COTI-NMeCy), and the non-substituted analogue (COTI-NH2) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe2 as an interesting new drug candidate with improved anticancer activity and resistance profile

Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance

COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe2 and COTI-NMeCy), and the non-substituted analogue (COTI-NH2) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe2 as an interesting new drug candidate with improved anticancer activity and resistance profile