Development, Synthesis and Characterization of bimetallic complexes as potential hypoxia-activated prodrugs with dual anticancer activity  Page description

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Details of project

 
Identifier
112317
Type K
Principal investigator Buglyó, Péter
Title in Hungarian Hipoxia aktivált, potenciálisan rákellenres hatású kétmagvú fémkomplexek kifejlesztése, előállítása és vizsgálata
Title in English Development, Synthesis and Characterization of bimetallic complexes as potential hypoxia-activated prodrugs with dual anticancer activity
Keywords in Hungarian ruténium, kobalt, rákellenes, oldategyensúly, szintézis, kristályszerkezet, redoxi, hipoxia-aktivált
Keywords in English ruthenium, cobalt, anticancer, solution equilibrium, synthesis, X-ray, redox, hypoxia-activated
Discipline
Inorganic Chemistry (Council of Physical Sciences)100 %
Ortelius classification: Organometallic Chemistry
Panel Chemistry 1
Department or equivalent Department of Inorganic and Analytical Chemistry (University of Debrecen)
Participants Bényei, Attila Csaba
Bihari, Zsolt
Farkas, Etelka
Földi-Bíró, Linda
Parajdi-Losonczi, Péter László
Starting date 2015-01-01
Closing date 2019-12-31
Funding (in million HUF) 24.282
FTE (full time equivalent) 11.97
state running project





 

Final report

 
Results in Hungarian
A kutatás során (O,O) donor hidroxamát, flavonolát, quinizarin és kinolon típusú ligandumok felhasználásával (közülük néhány korábban nem ismert új molekula) olyan új, vegyes ligandumú [Co(4N)(O,O)]n+ (4N = tripodális amin) kinetikailag inert komplexeket terveztünk, állítottunk elő és jellemeztünk, melyek várhatóan hipoxia-aktiváltak lehetnek. Megállapítottuk, hogy a kobalt +3 oxidációs állapotát stabilizáló 4N ligandum minősége (N donor típusa, kelát tagszáma) jelentősebben, de kisebb mértékben az O,O donor ligandum típusa illetve szubsztituáltsága is befolyásolja a komplexek redoxi sajátságait, így a komplexek szelektív redukciója (ami kinetikailag labilis komplexhez vezet) a rákos szövetekbeli redukciós potenciálhoz hangolható. Részletesen feltérképeztük félszendvics típusú fémorganikus ionok (Ru(II), Rh(III)) és a platina(II) modelljeként szolgáló Pd(II) oldatbeli kölcsönhatását olyan ligandumokkal, melyek a kétfémes komplexek ambidentát típusú ligandumainak (O,O), (N,N) vagy (O,O,N) donoratomú modelljei lehetnek. Mindezen ismereteket felhasználva az M/Co(III) (M = platinacsoportbeli fémion) kétfémes komplexek szintéziséhez szükséges ambidentát kelátképző ligandumokat (peptid/fenantrolin hidroxámsavak, peptid piridinonok, deferazirox hidroxámsavak) állítottunk elő, jellemeztük e ligandumokban a donoratomok fémion preferenciáját, vizsgáltuk a fenti fémionokkal képződő komplexeik kialakíthatóságát, stabilitását és elkészültek az első biológiai vizsgálatok is.
Results in English
By the use of (O,O) donor hydroxamates, flavonolates, quinizarines and quinolones (some of them newly synthesized) we have designed, synthesized and characterized novel, inert, mixed ligand [Co(4N)(O,O)]n+ (4N = tripodal amine) type complexes with likely hypoxia activation. It was found that both the type of the 4N donor (aliphatic versus aromatic N, size of the chelate) stabilizing the +3 oxidation state of Co as well as, in a lesser extent, the type and the presence of various substituents of the O,O donor ligand influence the redox features of the complexes therefore the selective reduction of the complexes resulting in the formation of labile Co(II) complexes can be tailored according to the redox potential of the cancer tissues. We have explored in detail the interaction of half-sandwich type Ru(II) and Rh(III) as well as Pd(II) (serving as model for Pt(II)) with ligands that can be (O,O), (N,N) or (O,O,N) donor building blocks of ambidentate ligands of heterobimetallic complexes. Based on this we have synthesized novel ambidentate ligands (peptide/phenanthroline hydroxamic acids, peptide pyridinones, deferasirox hydroxamic acids) necessary for the preparation of M/Co(III) (M = platinum group metal ion) heterobimetallic complexes and explored the metal ion preference of the donor atoms of these ligands. We have explored the optimal conditions for the formation of these complexes, their stability and screened some of them against cancer cells using biological assays.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=112317
Decision
Yes





 

List of publications

 
Zs. Bihari, Z. Nagy, P. Buglyó: [(η6-p-cym)Ru(H2O)3]2+ binding capability of N-methylimidazole to model the interaction between the metal ion and surface histidine residues of peptides, J. Organomet. Chem., 782, 82-88, 2015
J. Patalenszki, L. Bíró, A. C. Bényei, T. R. Muchova, J. Kasparkova, P. Buglyó: Half-sandwich complexes of ruthenium, osmium, rhodium and iridium with DL-methionine or S-methyl-L-cysteine: A solid state and solution equilibrium study, RSC Advances, 5, 8094-8107, 2015
P. Buglyó, K. Lénárt, M. Kozsup, A. C. Bényei, É. Kováts, I. Sóvágó, E. Farkas: [Pd(en)(H2O)2]2+ and [Pd(pic)(H2O)2]2+ complexation by monohydroxamic acids: A solution equilibrium and solid state approach, Polyhedron, 100, 392-399, 2015
P. L. Parajdi-Losonczi, A. C. Bényei, É. Kováts, I. Timári, T. R. Muchova, V. Novohradsky, J. Kasparkova, P. Buglyó: [(η6-p-cymene)Ru(H2O)3]2+ binding capability of aminohydroxamates — A solution and solid state study, J. Inorg. Biochem., 160, 236–245, 2016
Zs. Bihari, F. Vultos, C. Fernandes, L. Gano, I. Santos, J. D. G. Correia, P. Buglyó: Synthesis, characterization and biological evaluation of a 67Ga-labeled (eta6-Tyr)Ru(eta5-Cp) peptide complex with the HAV motif, J. Inorg. Biochem., 160, 189–197, 2016
P. Buglyó, E. M. Nagy, I. Sóvágó, A. Ozsváth, D. Sanna, E. Farkas: Metal ion binding capability of secondary (N-methyl) versus primary (N-H) dipeptide hydroxamic acids, Polyhedron, 110, 172-181, 2016
Zs. Bihari, V. Ugone, E. Garribba, N. Lihi, P. Buglyó: Complex formation between [(η6-p-cym)Ru(H2O)3]2+ and oligopeptides containing three histidyl moieties, J. Organomet. Chem., 823, 116-125, 2016
E. Farkas, P. Buglyó: Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest, Lead: Its Effects on Environment and Health, Metal Ions in Life Sciences, Eds. A. Sigel, H. Sigel, R. K. O. Sigel, Vol. 17, John Wiley & Sons, Chichester, UK, 2017
E. Farkas, P. Buglyó: Lead(II) Complexes of Amino Acids, Peptides, and Other Related Ligands of Biological Interest, Lead: Its Effects on Environment and Health, Metal Ions in Life Sciences, Eds. A. Sigel, H. Sigel, R. K. O. Sigel, Vol. 17, pp. 201–240, John Wiley & Sons, Chichester, UK, 2017
P. Buglyó, P. L. Parajdi-Losonczi, A. Cs. Bényei, N. Lihi, L. Bíró, E. Farkas: Versatility of coordination modes in complexes of monohydroxamic acids with half-sandwich type ruthenium, rhodium, osmium and iridium cations, ChemistrySelect, 2, 8127-8136, 2017
P. Buglyó, I. Kacsir, M. Kozsup, I. Nagy, S. Nagy, A. Cs. Bényei, É. Kováts, E. Farkas: Tuning the redox potentials of ternary cobalt(III) complexes containing various hydroxamates, Inorg. Chim. Acta, in press, 2018
Buglyó P., Farkas E.: Potenciálisan rákellenes hatású platinafémionok kölcsönhatása hidroxámsavakkal és származékaikkal, Magy. Kém. Foly., 123, 101-107, 2017
P. Buglyó, P. L. Parajdi-Losonczi, A. Cs. Bényei, N. Lihi, L. Bíró, E. Farkas: Versatility of coordination modes in complexes of monohydroxamic acids with half-sandwich type ruthenium, rhodium, osmium and iridium cations, ChemistrySelect, 2, 8127-8136, 2017
P. Buglyó, I. Kacsir, M. Kozsup, I. Nagy, S. Nagy, A. Cs. Bényei, É. Kováts, E. Farkas: Tuning the redox potentials of ternary cobalt(III) complexes containing various hydroxamates, Inorg. Chim. Acta, 472, 234-242, 2018
P. L. Parajdi-Losonczi, P. Buglyó, H. Skakalova, J. Kasparkova, N. Lihi, E. Farkas: Half-sandwich type rhodium–aminohydroxamate complexes: the role of the position of the amino group in metal ion binding, New J. Chem., 42, 7659-7670, 2018
B. D. Balogh, Zs. Bihari, P. Buglyó, G. Csire, Z. Kerekes, M. Lukács, I. Sóvágó, K. Várnagy: Metal binding selectivity of an N-terminally free multihistidine peptide, HAVAHHH-NH2, New J. Chem., 43, 907-916, 2019
M. Kozsup, E. Farkas, A. Cs. Bényei, J. Kasparkova, H. Crlikova, V. Brabec, P. Buglyó: Synthesis, characterization and biological evaluation of Co(III) complexes with quinolone drugs, J. Inorg. Biochem., közlésre elfogadva, 2019
M. Kozsup, E. Farkas, A. Cs. Bényei, J. Kasparkova, H. Crlikova, V. Brabec, P. Buglyó: Synthesis, characterization and biological evaluation of Co(III) complexes with quinolone drugs, J. Inorg. Biochem., 193, 94-105, 2019
A. Ozsváth, E. Farkas, R. Diószegi, P. Buglyó: Versatility and trends in the interaction between Pd(II) and peptidehydroxamic acids, New J. Chem., 43, 8239-8249, 2019
A. Ryan, M-C. Fitzgerald, A. Ozsváth, B. Twamley, P. Buglyó, B. Murphy, D. Griffith: Ni(II), Pd(II) and Pt(II) Complexes of the Hedgehog Pathway Inhibitor, GANT61-D, Inorg. Chem., 58, 16075-16086, 2019
A. Ozsváth, L. Bíró, E. M. Nagy, P. Buglyó, D. Sanna, E. Farkas: Trends and exceptions in the interaction of hydroxamic acid derivatives of common di-and tripeptides with some 3d and 4d metal ions in aqueous solution, Molecules, 24, 3941, 2019
M. Kozsup, O. Dömötör, S. Nagy, E. Farkas, É. A. Enyedy, P. Buglyó: Synthesis, Characterization and Albumin Binding Capabilities of Quinizarin Containing Ternary Cobalt(III) Complexes, J. Inorg. Biochem., 204, 110963, 2020
H. Crlikova, H. Kostrhunova, J. Pracharova, M. Kozsup, S. Nagy, P. Buglyó, V. Brabec, J. Kasparkova: Antiproliferative, DNA binding and cleavage properties of dinuclear Co(III) complexes containing the bioactive quinizarin ligand, J. Biol. Inorg. Chem., under revision, 2020





 

Events of the project

 
2018-12-04 10:39:22
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