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

Interconnects for DNA, quantum, in-memory and optical computing: insights from a panel discussion

The computing world is witnessing a proverbial Cambrian explosion of emerging paradigms propelled by applications such as Artificial Intelligence, Big Data, and Cybersecurity. The recent advances in technology to store digital data inside a DNA strand, manipulate quantum bits (qubits), perform logical operations with photons, and perform computations inside memory systems are ushering in the era of emerging paradigms of DNA computing, quantum computing, optical computing, and in-memory computing. In an orthogonal direction, research on interconnect design using advanced electro-optic, wireless, and microfluidic technologies has shown promising solutions to the architectural limitations of traditional von-Neumann computers. In this article, experts present their comments on the role of interconnects in the emerging computing paradigms and discuss the potential use of chiplet-based architectures for the heterogeneous integration of such technologies.This work was supported in part by the US NSF CAREER Grant CNS-1553264 and EU H2020 research and innovation programme under Grant 863337.Peer ReviewedPostprint (author's final draft

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

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

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

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

We report the synthesis and characterization of a group of benzoylhydrazones (Ln) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing distinct para substituents (R = H, Cl, F, CH3, OCH3, OH and NH2, for L1-7, respectively; in L8 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 L1 and L4) or as [Cu(Ln)]3 (n = 2, 3, 5, 6, 7 and 8). Single crystal X-ray diffraction studies were done for L5 and [Cu(L5)]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/H2O. Formation constants were determined for [Cu(LH)], [Cu(L)] and [Cu(LH−1)] for L = L1, L5 and L6, and also [Cu(LH−2)] for L = L6, and binding modes are proposed, [Cu(L)] predominating at physiological pH. The redox properties of complexes formed with L1, L5 and L6 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 L1, L3, L5 and L7, 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 IC50 values, and high induction of oxidative stress and DNA damage, which eventually lead to high rates of apoptosis

Interconnects for DNA, Quantum, In-Memory and Optical Computing: Insights from a Panel Discussion

The computing world is witnessing a proverbial Cambrian explosion of emerging paradigms propelled by applications, such as artificial intelligence, big data, and cybersecurity. The recent advances in technology to store digital data inside a deoxyribonucleic acid (DNA) strand, manipulate quantum bits (qubits), perform logical operations with photons, and perform computations inside memory systems are ushering in the era of emerging paradigms of DNA computing, quantum computing, optical computing, and in-memory computing. In an orthogonal direction, research on interconnect design using advanced electro-optic, wireless, and microfluidic technologies has shown promising solutions to the architectural limitations of traditional von-Neumann computers. In this article, experts present their comments on the role of interconnects in the emerging computing paradigms, and discuss the potential use of chiplet-based architectures for the heterogeneous integration of such technologies.Electronic

Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation

AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents - due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [I-125-Sar(1)-Ile(8)] AngII. Among the compounds tested, 19d and 9j molecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule 19d led to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest. (C) 2017 Elsevier Masson SAS. All rights reserved