Research of new, bioactive anellated nitrogen heterocycles  Page description

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Details of project

  
Identifier
48334
Type K
Principal investigator Hideg, Kálmán
Title in Hungarian Új bioaktív, anellált nitrogén heterociklusos vegyületek kutatása
Title in English Research of new, bioactive anellated nitrogen heterocycles
Panel Chemistry 2
Department or equivalent Institute of Organic Chemistry and Pharmaceutical Chemistry (University of Pécs)
Participants Balog, Mária
Berente, Zoltán
Bognár, Balázs
Kálai, Tamás
Kulcsár, Gyozo
Pápayné dr. Sár, Cecília
Starting date 2005-01-01
Closing date 2009-06-30
Funding (in million HUF) 15.746
FTE (full time equivalent) 5.14
state closed project





 

Final report

  
Results in Hungarian
A pályázat keretében számos új, stabilis nitroxid szabad gyökkel vagy annak redukált formájával módosított vegyületet állítottunk elő. Az előállított vegyületek kémiai sokfélesége három fő területre öszpontosul: új spinjelző vegyületek, ROS és RNS okozta károsodások kivédésére alkalmas vegyületek és szenzorvegyületek. Lipidek, nukleinbázisok fehérjékbe építhető paramágneses aminosavak spinjelölésére dolgoztunk ki jelölő molekulákat, új, click-reakcióban is alkalmazható spinjelző vegyületeket szintetizáltunk. A hidroxilamin reagáló csoporttal rendelkező új spinjrelző vegyületek alkalmasak karbonilcsoportot tartalmazó fehérje oldalláncok módosítására. Új, kinazolinon és benzimidazol alpú PARP-gátló és antioxidáns kettőshatású vegyületeket fejlesztettünk ki, továbbá az Ebselen, Verapamil és Amiodaron gyógyszermolekulákat módosítottuk nitroxidokkal. A módosított vegyületek megtartották eredeti hatásukat, de extra antioxidáns hatással/kisebb toxicitással rendelkeztek mint az alapmolekulák. Tovább folytattuk a danzil fluorofor csoportot tartamazó kettős (fluoreszcens és spin) redox szenzorok vizsgálatát. Új, pH érzékeny benzimidazol származékokat szintetizáltunk. Módszert dolgoztunk ki izoindolin nitroxidok szintézisére és heterociklusokkal anellált nitroxidok előállítására. A projekt során ill. az előző pályázatok során elért eredményeinket két összegző cikkben ( Journal of Hetreocyclic Chemistry és Journal of Cardiovascular Toxicology) foglaltuk össze.
Results in English
In the frame of this project several new compounds were synthesized containing nitroxide or its precursor. The main emphases were on: new spin labels, ROS and RNS radical scavengers capable of decreasing pathological processes and sensor compounds. New spin labels were incorporated into lipids, nucleic acids and proteins. Paramagnetic click chemistry partners were developed which can be incorporated by 1,3-dipolar cycloaddition reactions. New O-alkylated hydroxylamines were synthesized to modify proteins containing carbonyl group (may be formed during oxidative stress). New dual active (PARP inhibitor and antioxidant) benzimidazole and quinazoline compounds were synthesized and tested. This phenomenon was extended on Ebselen and Amiodarone drugs with paramagnetic function keeping in mind that modified compound need to treasure the original activity with extra antioxidant activity without reducing therapeutic index. Sensor compounds: fluorescent/spin ROS and EPR active pH sensors were obtained. New synthetic procedures were introduced for synthesis of isoindolines and nitroxides condensed with heterocycles. We published a new nitroxide chemistry review. A short review article was also published on the importance of dual activity in reducing the toxic side effects of anthracycline antitumor drugs (such as Doxorubicin).
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=48334
Decision
Yes





 

List of publications

  
Bridges, M. D.; Hideg, K.; Hubbell, W. L.: Resolving conformational and rotameric exchange in spin labelled proteins using saturation recovery EPR, Appl. Magn. Resonance (in press), 2009
Bordington, E.;Brutlach, H.; Urban, L.; Hideg, K.; Savitsky, A., Schnegg, A.; Gast, P.; Engelhard, M.; Groenen, E. J. J.; Möbius, K.; Steinhoff, H-J.: Heterogeneity in the nitroxide micro-environment: polarity and proticity effects in spin labelled proteins studied by multifrequency EPR., Appl, Magn. Resonance (in press), 2009
Fleissner, M.R.; Brustad, E. M.; Kálai, T.; Altenbach, C.; Cascio, D.; Peters, F.; Hideg, K. Schultz, P. G.; Hubbell, W. L.: Site-directed Spin Labeling of a genetically Encoded Unnatural Amino Acid, P. Natl. Acad. Sci. USA (in press), 2009
Hideg, K.; Kálai, T. Sümegi, B: Process for the preparation of 4-carboxamidobenzimidazole derivatives as PARP inhibitors and antioxidants., HU 200400883 A2 20070928, 2007
Hideg, K.: Process for the preparation of benzo-isoselenazoles and pharmaceutical compositions containing them., HU 200105050 A2 20050428, 2005
Hideg, E.; Kálai, T.; Kos, P.; Asada, K.; Hideg, K.: Singlet Oxygen in Plants - its Significance and Possible Detection with Double (Fluorescent and Spin) Indicator Reagents., Photochem. Photobiol. 82, 1211-1218, 2006
Kálai, T.; Várbíró, G.; Bognár, Z.; Pálfi, A.; Hantó, K.; Bognár, B.; Ősz, E.; Sümegi, B.; Hideg, K.: Synthesis and evaluation of the permeability transition inhibitory characteristics of paramagnetic and diamagnetic amiodarone derivatives, Bioorganic & Medicinal Chemistry 13, 2629-2636., 2005
Becker C. F. W.; Lausecker, K.; Balog, M.; Kálai, T.; Hideg, K.; Steinhoff, H-J.; Engelhard, M.: Incorporation of spin labelled amino acid into proteins, Magn. Reson. Chem. 43. S34-S39., 2005
Pálfi, A.; Tóth, A.; Kulcsár, Gy.; Hantó, K.; Deres, P.; Bartha, É.; Halmosi, R.; Szabados, E.; Czopf, L.;Kálai, T.; Hideg, K.; Sümegi, B.;Tóth, K.: The Role of Akt and Mitogen-Activated Protein Kinase Systems in the Protective Effect Poly(ADP-Ribose) Polymerase Inhibition in Lagendorff Perfused and in Isoproterenol-D, Journal of Pharmacology and Experimental Therapeutics 315, 273-282., 2005
Kálai, T.; Mugesh, G.; Roy, G.; Sies, H.; Berente, Z.; Hideg, K.: Combining benzol[d]isoselenazol-3-ones with sterically hindered alicyclic amines and nitroxides: enhanced activity as glutathione peroxidase mimics, Org. Biomol. Chem. 3, 3564-3569., 2005
Kálai, T.; Jekő, J.; Berente, Z.; Hideg, K.: Palladium-Catalyzed Cross-Coupling Reactions of Paramagnetic Vinyl Bromides and Paramagnetic Boronic Acids., Synthesis 439-446, 2006
Kovács, K.; Sümegi, B.; Tóth, A.; Deres, P.; Kálai, T.; Hideg, K.; Gallyas, F.: Critical role of PI3-kinase/Akt activation in the PARP inhibitor induced heart function recovery during ischemia-reperfusion, Biochem. Pharmacol. 71, 441-452, 2006
Deres, P.; Halmosi, R.; Tóth, A.; Kovács, K.; Pálfi, A.; Habon, T.; Czopf, L.; Kálai, T.; Hideg, K.; Sümegi, B.; Tóth, K.: Prevention of Doxorubicin-Induced Acute Cardiotoxicity by an Experimental Antioxidant Compound, J. Cardiovasc. Pharmacol. 45(1), 36-43., 2005
Sár, P. C.; Ősz, E.; Jekő, J.; Hideg, K.;: Synthesis of Spiro[pyrrolidine-2,2’-adamantane] Nitrones and Nirtoxides, Synthesis, 255-260, 2005
Hideg, K.; Kálai, T.; Sár, P. C.: Recent results in chemistry and biology of nitroxides, J. Heterocyclic Chem. 42, 437-450., 2005
Kálai, T.; Bognár, B.; Jekő, J.; Hideg, K.: Synthesis of new, paramagnetically modified heterocycles, Synthesis, 2573-2579, 2006
Goldstein, S.; Samuni, A.; Hideg, K.; Merényi, G.: Structure-Activity Relationship of Cyclic Nitroxides as SOD Mimics and Scavengers of Nitrogen Dioxide, J. Phys. Chem. A. 110, 3679-3685., 2006
Kutala, V. K.; Khan, M. ; Mandal, R.; Ganesan, L. P.; Tridandapani, S.; Kálai, T.; Hideg, K.; Kuppusamy, P.: Attenuation of Myocardial Ischemia-Reperfusion Injury by Trimetazidine Derivatives Functionalized with Antioxidant Properties, J. Pharm. Exp. Ther. 317, 921-928., 2006
Cai, Q.; Kusnetzow, A. K.; Hubbell, W. L.; Haworth, I. S.; Gacho, G. P. C.; Eps, N. V.; Hideg, K.; Chambers, E. J.; Qin, P. Z.: Site-directed spin labeling measurements of nanometer distances in nucleic acids using a sequence-independent nitroxide probe, Nucl. Acid Res. 34, 4722-4730., 2006
Kálai, T.; Khan, M.; Balog, M.; Kutala, K. V.; Kuppusamy, P.; Hideg, K.: Structure-activity studies on the protection of Trimetazidine derivatives modified with nitroxides and their precursor from myocardial ischemia-reperfusion injury, Bioorg. Med. Chem. 14, 5510-5516., 2006
Shvetsov, A.; Stamm, J. D.; Phillips, M.; Warshaviak, D.; Altenbach, C.; Rubenstein, P. A.; Hideg, K.; Hubbell, W. L.; Reisler, E.: Conformational Dynamics of Loop 267-274 in G- and F-actin, Biochemistry 45, 6541-6549., 2006
Lozinsky, E.; Iametti, S.; Barbiroli, A.; Likhtenshtein, G. I.; Kálai, T.; Hideg, K.; Bonomi, .F.: Structural Features of Transiently Modified Beta-Lactoglobulin Relevant to the Stable Binding of Large Hydrophobic Molecules, The Protein J. 25, 1-15., 2006
Pálfi, A.; Tóth, A.; Hantó, K.; Deres, P.; Szabados, E.; Szereday, Z.; Kulcsár, Gy.; Kálai, T.; Hideg, K.; If. Gallyas, F.; Sümegi, B.; Tóth, K.; Halmosi, R.: PARP inhibition prevents postinfarction myocardial remodelling and heart failure via the protein kinase C/glycogen synthase kinase-3-beta pathway, J. Mol. Cell. Cardiology 41, 149-159., 2006
Bognár, Z.; Kálai, T.; Pálfi, A.; Hantó, K.; Bognár, B.; Márk, L.; Szabó, Z.; Tapodi, A.; Radnai, B. ; Sárszegi, Zs.; Szántó, Á.; Jr. Gallyas, F.; Hideg, K.; Sümegi, B.; Várbíró, G.: A novel SOD-mimetic permeability transition inhibitor agent protects ischemic heart by inhibiting both apoptotic and nectrotic cell death., Free Rad. Biol. Med. 41, 835-848., 2006
Kálai, T.; Hideg, K.: Synthesis of New BODIPY-based Sensors and Labels, Tetrahedron 62, 10352-10360., 2006
Raju, N.; Spacek, T.; Jezek, J.; Leinisch, F.; Hideg, K.; Jezek, P.; Trommer, W. E.: Fatty Acid Binding Site of Mitochondrial Uncoupling protein UCP2 as Probed by EPR spectroscopy of Spin-labeled Fatty Acids, Applied Magnetic Resonance, 30, 373-383, 2006
Balog, M.; Abé, C.; Kálai, T.; Steinhoff, H. J.; Jekő, J.; Hideg, K.: Synthesis of New Paramagnetic Fatty Acids and Lipophilic Spin Labels, Synthesis. 1663-1670, 2007
Hideg, K.; Kálai, T.: Novel Antioxidants in anthracycline cardiotoxicity, Cardiovascular Toxicol, 7, 160-164, 2007
Cai, Q.; Kusnetzow. A. K.; Hideg, K.; Price, E. A.; Hawort, I. S.; Qin, P. Z.: Nanomewter Distance Measurements in RNA Using Site-Directed Spin Labeling, Biophysical Journal, 93, 2110-2117, 2007
Selvendiran, K.; Tong, L.; Vishwanath, S.; Bratasz, A.;Trigg. N. J.; Kutala, V. K.; Hideg. K.; Kuppusamy, P.: EF24 Induces G2/M Arrest and Apoptosis in Cisplatin-Resistant Human Ovarian Cancer Cells by Increasing Pten Expression, J. Biol. Chem. 282, 28609-28618, 2007
Guo, Z.; Hideg, K.; Kálai, T.; Cascio, D.; Hubbell, W. L.: Structural determinants of nitroxide motion in spin-labeled proteins: tertiary contact and solvent inaccessible sites in helix G of T4 lysozyme, Protein Science 16, 1069-1086, 2007
Mandal, R.; Kutala, V. K.; Khan, M.; Mohan, I. K.; Varadharaj, S.; Sridhar, A.; Carnes, C. A., Hideg. K.; Kuppusamy, P.: N-hydroxy-pyrroline Modification of Verapamil Exhibits Antioxidant Protection of the Heart against Ischemia/Reperfusion-induced Cardiac Dysfunction without compromisin, J. Pharm. Exp. Ther., 323, 119-127, 2007
Subramaniam, D.; May, R.; Sureban, S. M.; Lee, K. B.; George, R.; Kuppusamy, P.; Ramanujam, R. P.; Hideg, K.; Dieckgraefe, B. K.; Houchen, C. W.; Anant, S.: Diphenyl Difluroketone (EF24): a Curcumin Derivative with Potent In Vivo Anti-Cancer Activity, Cancer Research 68, (6), 1962-1969, 2008
Kálai.,T.; Schindler, J.; Balog, M.; Fogassy, E.; Hideg, K.: Synthesis and resolution of new paramagnetic α-amino acids, Tetrahedron, 64, 1094-1100., 2008
Guo, Z.; Casio, D.; Hideg, K.; Hubbell, W. L.: Structural determinants of nitroxide motion in spin-labeled proteins: Solvent-exposed sites in helix B of T4 lysozyme, Protein Science 17, 228-239, 2008
Bognár, B. ; Kálai,T.; Hideg, K.: Synthesis of Benzimidazoles Condensed with, or Linked to, Nitroxides or Heterocyclic N-Oxides, Synthesis 2349-2445, 2008
Mohan, I. K.; Kahn, M.; Wisel, S.; Selvendiran, K.; Sridhar, A.; Carnes, C. A.; Bognár, B.; Kálai, T.; Hideg, K.; Kuppusamy, P.: Cardioprotection by HO-4038, a novel verapamil derivative, targeted against ischemia and reperfusion-mediated acute myocardial infarction, Am. J. Physiol. Heart Circ. Physiol. 296, 140-151., 2009
Zielke, V.; Eickmeier, H.; Hideg, K.; Reuter, H.; Steinhoff, H.J.: A commonly used spin label: S-(2,2,5,5-tetramethyl-1-oxyl-Δ3-pyrrolin-3-ylmethyl) methanethiosulfonate, Crystal Structure Communications 64, 586-589., 2008
Bartha, É.; Kiss, N. Gy.; Kálmán, E.; Kulcsár, Gy.; Kálai, T.; Hideg, K.; Habon, T.; Sümegi, B.; Tóth, K.; Halmosi, R.: Effect of L-2286, a Poly(ADP-ribose)polymerase Inhibitor and Enalapril on Myocardial Remodeling and Heart Failure, J. Cardiovacc. Pharm. 52, 253-261, 2008
Tóth, S.; Quintavalle, D.; Náfrádi, B.; Forró, L.; Korecz, L.; Rockenbauer, A.; Kálai, T.; Hideg, K.; Simon, F.: Stability and electronic properties of magnetic peapods, Phys. Stat. Sol (b). 245, 2034-2037., 2008
Kálai, T.; Jekő,J.; Hideg, K: Synthesis of Isoindoline Nitroxides by Elekrocyclic Reactions, Synthesis 2591-2595, 2009
Kálai, T.; Balog, M.; Szabó, A.; Gulyás, G.; Jekő, J.; Sümegi, B.; Hideg, K.: New Poly(ADP-ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-carboxamidobenzimidazol-2-yl pyrroline and -tetrahydropyridine Nitroxides and their Precursors, J. Med. Chem. 52, 1619-1629., 2009
Kálai, T.; Hubbel, W. L.; Hideg, K.: Click Reactions with Nitroxides, Synthesis, 1336-1341, 2009
Selvendrian, K.; Kuppusamy, M. L.; Bratasz, A.; Tong, L.; Rivera, B. K.; Rink, C.; Sen, C. K.; Kálai, T.; Hideg, K.; Kuppusamy, P.: Inhibition of vascular smooth-muscle-cell proliferation and arterial restenosis by HO-3867, a novel synthetic, J. Pharm. Exp. Ther. 329, 959-966., 2009
Wisel, S.; Khan, M.; Kuppusamy, M. L.; Mohan, I. K.; Chacko, S. M.; Rivera, B. K.; Sun, B. C.; Hideg, K.; Kuppusamy, P.: Pharmacological preconditioning of mesenchymal stem cell with Trimetazidine protects hypoxic cells, J. Pharm. Exp. Ther. 329, 543-550., 2009
Bartha, E.; Solti, I.; Kereskai, L.; Lantos, J.; Plozer, E.; Magyar, K.; Szabados, E.; Kalai, T. Hideg, K.; Halmosi, R.; Sumegi, B.; Toth, K.: IPARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats, Cardiovasc. Res. 83, 501-510, 2009
Popova, A. M.; Kalai, T.; Hideg, K.; Qin, P. Z.: Site-Specific DNA Structural and Dynamic Features Revealed by Nucleotide-Independent Nitroxide Probes, Biochemistry 48, 8540-8550, 2009



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