Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

New Copper Compounds with Antiplatelet Aggregation Activity

Author(s): Mirthala Flores-García, Juan Manuel Fernández-G., Cristina Busqueta-Griera, Elizabeth Gómez, Simón Hernández-Ortega, Jean Christian Daniel Lamothe-Flores, Virginia Gómez-Vidales, Ana María Mejía-Domínguez, Eduardo Anglés-Cano and Aurora de la Peña-Díaz*

Volume 15, Issue 8, 2019

Page: [850 - 862] Pages: 13

DOI: 10.2174/1573406415666190222123207

Price: $65

Abstract

Background: Ischemic heart disease, cerebrovascular accident, and venous thromboembolism have the presence of a thrombotic event in common and represent the most common causes of death within the population.

Objective: Since Schiff base copper(II) complexes are able to interact with polyphosphates (PolyP), a procoagulant and potentially prothrombotic platelet agent, we investigated the antiplatelet aggregating properties of two novel tridentate Schiff base ligands and their corresponding copper( II) complexes.

Methods: The Schiff base ligands (L1) and (L2), as well as their corresponding copper(II) complexes (C1) and (C2), were synthesized and characterized by chemical analysis, X-ray diffraction, mass spectrometry, and UV-Visible, IR and far IR spectroscopy. In addition, EPR studies were carried out for (C1) and (C2), while (L1) and (L2) were further analyzed by 1H and 13C NMR. Tests for antiplatelet aggregation activities of all of the four compounds were conducted.

Results: X-ray diffraction studies show that (L1) and (L2) exist in the enol-imine tautomeric form with a strong intramolecular hydrogen bond. NMR studies show that both ligands are found as enol-imine tautomers in CDCl3 solution. In the solid state, the geometry around the copper(II) ion in both (C1) and (C2) is square planar. EPR spectra suggest that the geometry of the complexes is similar to that observed in the solid state by X-ray crystallography. Compound (C2) exhibited the strongest antiplatelet aggregation activity.

Conclusion: Schiff base copper(II) complexes, which are attracting increasing interest, could represent a new approach to treat thrombosis by blocking the activity of PolyP with a potential anticoagulant activity and, most importantly, demonstrating no adverse bleeding events.

Keywords: Copper(II) complexes, antiplatelet activity, polyphosphates, X-ray diffraction, X-ray crystallography, Schiff base.

Graphical Abstract
[1]
Thrombosis: a major contributor to the global disease burden. J. Thromb. Haemost., 2014, 12(10), 1580-1590.
[http://dx.doi.org/10.1111/jth.12698] [PMID: 25302663]
[2]
Heit, J.A. Epidemiology of venous thromboembolism. Nat. Rev. Cardiol., 2015, 12(8), 464-474.
[http://dx.doi.org/10.1038/nrcardio.2015.83] [PMID: 26076949]
[3]
Semple, J.W.; Italiano, J.E., Jr; Freedman, J. Platelets and the immune continuum. Nat. Rev. Immunol., 2011, 11(4), 264-274.
[http://dx.doi.org/10.1038/nri2956] [PMID: 21436837]
[4]
Gremmel, T.; Frelinger, A.L., III; Michelson, A.D. Platelet Physiology. Semin. Thromb. Hemost., 2016, 42(3), 191-204.
[http://dx.doi.org/10.1055/s-0035-1564835] [PMID: 26926581]
[5]
Pluthero, F.G.; Kahr, W.H.A. The Birth and Death of Platelets in Health and Disease. Physiology (Bethesda), 2018, 33(3), 225-234.
[http://dx.doi.org/10.1152/physiol.00005.2018] [PMID: 29638183]
[6]
Morrissey, J.H.; Smith, S.A. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J. Thromb. Haemost., 2015, 13(Suppl. 1), S92-S97.
[http://dx.doi.org/10.1111/jth.12896]
[7]
Smith, S.A.; Choi, S.H.; Collins, J.N.; Travers, R.J.; Cooley, B.C.; Morrissey, J.H. Inhibition of polyphosphate as a novel strategy for pre-venting thrombosis and inflammation. Blood, 2012, 120(26), 5103-5110.
[http://dx.doi.org/10.1182/blood-2012-07-444935] [PMID: 22968458]
[8]
Gomes, F.M.; Carvalho, D.B.; Peron, A.C.; Saito, K.; Miranda, K.; Machado, E.A. Inorganic polyphosphates are stored in spherites within the midgut of Anticarsia gemmatalis and play a role in copper detoxification. J. Insect Physiol., 2012, 58(2), 211-219.
[http://dx.doi.org/10.1016/j.jinsphys.2011.09.008] [PMID: 21946413]
[9]
Shen, Z.Q.; Liang, Y.; Chen, Z.H.; Liu, W.P.; Duan, L. Effects of copper-aspirin complex on platelet aggregation and thrombosis in rabbits and mice. J. Pharm. Pharmacol., 1998, 50(11), 1275-1279.
[http://dx.doi.org/10.1111/j.2042-7158.1998.tb03345.x] [PMID: 9877314]
[10]
Ahmed, M.; Ali, M.; Ayatollahi, S.A.; Esfahanizadeh, M.; Kobarfard, F.; Hasan, A.; Khan, K.M.; Haider, S.M. Short Communication - Synthesis of drug metal complexes and their influence on human platelet aggregation. Pak. J. Pharm. Sci., 2018, 31(2), 587-591.
[PMID: 29618452]
[11]
Garnovskii, A.D.; Vasilchenko, I.S.; Garnovskii, D.A.; Khari-sov, B. Molecular design of mononuclear complexes of acyclic Schiff-base ligands. J. Coord. Chem., 2009, 62, 151-204.
[http://dx.doi.org/10.1080/00958970802398178]
[12]
Raman, N.; Johnson, S.; Sakthivel, A. Transition metal complexes with Schiff-base ligands: 4-aminopyridine based derivatives-a review. J. Coord. Chem., 2009, 62, 691-709.
[http://dx.doi.org/10.1080/00958970802326179]
[13]
Tezer, N.; Karakus, N. Theoretical study on the ground state intramolecular proton transfer (IPT) and solvation effect in two Schiff bases formed by 2-aminopyridine with 2-hydroxy-1- naphthaldehyde and 2-hydroxy salicylaldehyde. J. Mol. Model., 2009, 15(3), 223-232.
[http://dx.doi.org/10.1007/s00894-008-0397-6] [PMID: 19048313]
[14]
Grivani, G.; Tahmasebi, V. DehnoKhalaji, A.; Eigner, V.; Dušek, M. Synthesis, characterization, crystal structure, catalytic activity in oxi-dative bromination, and thermal study of a new oxidovanadium Schiff base complex containing O, N-bidentate Schiff base ligand. J. Coord. Chem., 2014, 67, 3664-3677.
[http://dx.doi.org/10.1080/00958972.2014.960405]
[15]
Hijji, Y.M.; Bararea, B.; Kennedy, A.P.; Butcher, R. Synthesis and photophysical characterization of a Schiff base as anion sensor. Sens. Actuators B Chem., 2009, 136, 297-302.
[http://dx.doi.org/10.1016/j.snb.2008.11.045]
[16]
Aksuner, N.; Henden, E.; Yilmaz, I.; Cukurovali, A. Selective optical sensing of copper(II) ions based on a novel cyclobutane-substituted Schiff base ligand embedded in polymer films. Sens. Actuators B Chem., 2008, 134, 510-515.
[http://dx.doi.org/10.1016/j.snb.2008.05.041]
[17]
Xiong, Y.; Li, W.H.N.N. ′-(3-Bromo-2-hydroxybenzylidene) isonicotinohydrazide and its oxovanadium(V) complex: synthesis, structures, and catalytic properties. J. Coord. Chem., 2014, 67, 3279-3287.
[http://dx.doi.org/10.1080/00958972.2014.963065]
[18]
Hao, L.; Zi-Jian, Y.; Dong, L.; Guo-Xin, J. Multi-component coordination-driven self-assembly toward heterometallic mac-rocycles and cages. Coord. Chem. Rev., 2015, 293, 139-157.
[19]
Jing, Y.; Xiaoqi, L.; Zhen-liang, X.; Haitao, X. Cobalt(II) met-al–organic framework micro-nanoparticles: Molecular self-assembly from layers to micropores showing the conjunctive orientation of carboxyl groups. J. Mol. Struct., 2015, 1093, 162-165.
[http://dx.doi.org/10.1016/j.molstruc.2015.03.040]
[20]
Haeili, M.; Moore, C.; Davis, C.J.; Cochran, J.B.; Shah, S.; Shrestha, T.B.; Zhang, Y.; Bossmann, S.H.; Benjamin, W.H.; Kutsch, O.; Wolschendorf, F. Copper complexation screen reveals compounds with potent antibiotic properties against methicillin-resistant Staphylo-coccus aureus. Antimicrob. Agents Chemother., 2014, 58(7), 3727-3736.
[http://dx.doi.org/10.1128/AAC.02316-13] [PMID: 24752262]
[21]
Lobana, T.S.; Indoria, S.; Jassal, A.K.; Kaur, H.; Arora, D.S.; Jasinski, J.P. Synthesis, structures, spectroscopy and antimicrobial proper-ties of complexes of copper(II) with salicylaldehyde N-substituted thiosemicarbazones and 2,2′-bipyridine or 1,10-phenanthroline. Eur. J. Med. Chem., 2014, 76, 145-154.
[http://dx.doi.org/10.1016/j.ejmech.2014.02.009] [PMID: 24583354]
[22]
Leon, I.E.; Cadavid-Vargas, J.F.; Di Virgilio, A.L.; Etcheverry, S.B. Vanadium, ruthenium and copper compounds: A new class of non-platinum metallodrugs with anticancer activity. Curr. Med. Chem., 2017, 24(2), 112-148.
[http://dx.doi.org/10.2174/0929867323666160824162546] [PMID: 27554807]
[23]
Tisato, F.; Marzano, C.; Peruzzo, V.; Tegoni, M.; Giorgetti, M.; Damjanovic, M.; Trapananti, A.; Bagno, A.; Santini, C.; Pellei, M.; Porchia, M.; Gandin, V. Insights into the cytotoxic activity of the phosphane copper(I) complex.[Cu(thp)4][PF6]. J. Inorg. Biochem., 2016, 165, 80-91. [Cu(thp)4]. [PF6].
[http://dx.doi.org/10.1016/j.jinorgbio.2016.07.007] [PMID: 27449160]
[24]
Pradeep, K.M.; Tejaswi, S.; Rambabu, A.; Kalalbandi, V.K.; Shivaraj, H. Synthesis, crystal structure, DNA binding and cleavage studies of copper(II) complexes with isoxazole Schiff bases. Polyhedron, 2015, 102, 111-120.
[http://dx.doi.org/10.1016/j.poly.2015.07.052]
[25]
Fang, N.; Ke-Xiang, Y.; Linhan, P.; Dan, Q.; Xinlu, Z.; Zhon-glu, Y. Synthesis and structural characterization of Schiff base copper(II) complexes with Helicobacter pylori urease inhibitory activities. Inorg. Chim. Acta, 2015, 435, 299-304.
[http://dx.doi.org/10.1016/j.ica.2015.07.014]
[26]
Li, N.; Kang, G.; Gui, L.; Zhao, M.; Wang, W.; Zhang, J.; Yue, Y.F.; Peng, S. Novel Cu(II)-RGD-octapeptides: Synthesis, coordination mode, in vitro anti-platelet aggregation/in vivo anti-thrombotic evaluation and correlation of sequence with nano-structure. Nanomedicine (Lond.), 2011, 7(4), 403-409.
[http://dx.doi.org/10.1016/j.nano.2011.01.005] [PMID: 21272663]
[27]
Garnovskii, A.D.; Sadimenko, A.P.; Sadimenko, M.I.; Gar-novskii, D.A. Common and less-common coordination modes of the typical chelating and heteroaromatic ligands. Coord. Chem. Rev., 1998, 173, 31-77.
[http://dx.doi.org/10.1016/S0010-8545(98)00084-8]
[28]
Garnovskii, A.D.; Vasilchenko, I.S. Tautomerism and various coordination modes of typical chelating ligands with metals. Russ. Chem. Rev., 2005, 74, 193-215.
[http://dx.doi.org/10.1070/RC2005v074n03ABEH001164]
[29]
Holm, R.H.; O’ Connor, M.J. The stereochemistry of bis-chelate metal(II) complexes. Prog. Inorg. Chem., 1971, 14, 241-401.
[http://dx.doi.org/10.1002/9780470166154.ch5]
[30]
Maslen, H.S.; Waters, T.N. The conformation of Schiff-base complexes of copper(II): a stereo-electronic view. Coord. Chem. Rev., 1975, 17, 137-176.
[http://dx.doi.org/10.1016/S0010-8545(00)80302-1]
[31]
Yokoi, H. ESR and optical-absorption studies of various Bis(N-Salicyli-denealkylaminato) copper (II) complexes with tetrahedrally-distorted coordination geometry. Bull. Chem. Soc. Jpn., 1974, 47, 3037-3040.
[http://dx.doi.org/10.1246/bcsj.47.3037]
[32]
Villagran, M.; Caruso, F.; Rossi, M.; Zagal, J.H.; Costamagna, J. Substituent effects on structural, electronic, and redox properties of Bis(N-alkyl-2-oxy-1-naphthal-diminato) cop-per(II) complexes revisited- inequivalence in solid- and solution-state structures by elec-tronic spectroscopy and X-ray dif-fraction explained by DFT. Eur. J. Inorg. Chem., 2010, 2010, 1373-1380.
[http://dx.doi.org/10.1002/ejic.200900298]
[33]
Fernández-G, J.M.; Rosales, M.J.; Rubio-Arroyo, M.F.; Salcedo, R.; Toscano, R.A.; Vela, A. Synthesis, crystal structure, and EHMO cal-culations for the Ni(II) complexes of imines derived from salicylaldehyde, 2-hydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthaldehyde. Inorg. Chem., 1987, 26, 349-357.
[http://dx.doi.org/10.1021/ic00250a003]
[34]
Sonn, A.; Müller, E. Übereineneuemethodezurumwandlung von carbonsäuren in aldehyde. Ber. Dtsch. Chem. Ges., 1919, 52, 1927-1934.
[http://dx.doi.org/10.1002/cber.19190521002]
[35]
Khorana, M.L.; Pandit, S.Y. Synthesis of β-naphthol derivatives. Part VI. 3-alkyl-β-nahthols, 2-hydroxy-3-naphthaldehyde and its deriva-tives. J. Indian Chem. Soc., 1963, 40, 789-793.
[36]
Aue, W.P.; Bartholdi, E.; Ernst, R.R. Two-dimensional spec-troscopy. Application to nuclear magnetic resonance. J. Chem. Phys., 1976, 64, 2229-2246.
[http://dx.doi.org/10.1063/1.432450]
[37]
Sorensen, O.W.; Rance, M.; Ernst, R.R. z Filters for purging phase- or multiplet-distorted spectra. J. Magn. Reson., 1984, 56, 527-534.
[38]
Sheldrick, G.M. SHELXL-97. Program for Crystal Structure Refinement. Version 97-1. InstitutAnorg. Chemie; University of Gottingen: Germany, 1997.
[39]
International Tables for X-ray Crystallography; Kluwer Academic Publisher: Dordrecht, 1992.
[40]
Dayagi, S.; Degani, S.Y. The Chemistry of the Carbon-Nitrogen Double Bond. S; Wiley/Interscience: London, 1970.
[41]
Eichhorn, G.L.; Marchand, N.D. The stabilization of the sa-licylaldehyde-glycine Schiff base through metal complex for-mation. J. Am. Chem. Soc., 1956, 78, 2688-2691.
[http://dx.doi.org/10.1021/ja01593a009]
[42]
Tümer, M.; Çelik, C.; Köksal, H. Transition metal complexes of bidentate Schiff base ligands. Transit. Metal. Chem., 1999, 24, 525-532.
[http://dx.doi.org/10.1023/A:1006982622965]
[43]
Percy, G.C.; Thornton, D.A. N-alkyl salicilaldimine complex-es: Infrared and PMR spectra of the ligands and vibrational frequencies of their metal(II) chelates. J. Inorg. Nucl. Chem., 1972, 34, 3369-3376.
[http://dx.doi.org/10.1016/0022-1902(72)80231-8]
[44]
Zishen, W.; Zhiping, L.; Zhenhuan, Y. Synthesis, characterization and antifungal activity of glycylglycine Schiff base complexes of 3d transition metal ions. Transit. Metal. Chem., 1993, 18, 291-294.
[http://dx.doi.org/10.1007/BF00207949]
[45]
Allen, F.H.; Kennard, O.; Watson, D.G.; Brammer, L.; Orpen, A.G.; Taylor, R. Tables of bond lengths determined by X-Ray and neutron diffraction methods. Part 1. Bond lenghts in or-ganic compounds. J. Chem. Soc., Perkin Trans. 2, 1987, S1-S19.
[http://dx.doi.org/10.1039/p298700000s1]
[46]
Sang, Y.L.; Lin, X.S. Synthesis and crystal structures of two Schiff base copper(II) complexes derived from 4-chloro-2-[(2-morpholin-4-yl-ethylimino)methyl]phenol. Russ. J. Coord. Chem., 2010, 36, 472-476.
[http://dx.doi.org/10.1134/S1070328410060096]
[47]
Fernández-G, J.M.; del Río-Portilla, F.; Quiroz-García, B.; Toscano, R.A.; Salcedo, R. The structures of some ortho-hydroxy Schiff base ligands. J. Mol. Struct., 2001, 561, 197-297.
[http://dx.doi.org/10.1016/S0022-2860(00)00915-7]
[48]
Akitsu, T.; Einaga, Y. Bis(5-chloro-N-isopropylsalicyldenaminato-κ2/V,O) -copper(II). Acta Crystallogr. Sect. E Struct. Rep. Online, 2004, 60, 4.
[http://dx.doi.org/10.1107/S1600536804005938]
[49]
Razniewska-Lazecka, S.G.; Dambska, A.; Janowski, A. 13C NMR spectra of some o-carbonyl derivatives of naphtols. Magn. Reson. Chem., 1986, 24, 365-367.
[http://dx.doi.org/10.1002/mrc.1260240421]
[50]
Labanowska, M.; Bidzinska, E.; Para, A.; Kurdziel, M. EPR investigation of Cu(II)-complexes with nitrogen derivatives of dialdehyde starch. Carbohydr. Polym., 2012, 87, 2605-2613.
[http://dx.doi.org/10.1016/j.carbpol.2011.11.034]
[51]
Corona-de-la-Peña, N.; Uribe-Carvajal, S.; Barrientos-Rios, R.; Matias-Aguilar, L.; Montiel-Manzano, G.; Majluf-Cruz, A. Polyamines inhibit both platelet aggregation and glycoprotein IIb/IIIa activation. J. Cardiovasc. Pharmacol., 2005, 46(2), 216-221.
[http://dx.doi.org/10.1097/01.fjc.0000171753.43564.7c] [PMID: 16044034]
[52]
Béreau, V.; Rey, J.; Deydier, E.; Marrot, J. Synthesis and characterization of new copper(II) and nickel(II) complexes of 3-(2′-hydroxyphenyl)-1,2,4-triazine derivatives. Inorg. Chim. Acta, 2003, 351, 389-394.
[http://dx.doi.org/10.1016/S0020-1693(03)00192-0]
[53]
Jennings, L.K. Role of platelets in atherothrombosis. Am. J. Cardiol., 2009, 103(3)(Suppl.), 4A-10A..
[http://dx.doi.org/10.1016/j.amjcard.2008.11.017] [PMID: 19166707]
[54]
da Silveira, V.C.; Luz, J.S.; Oliveira, C.C.; Graziani, I.; Ciriolo, M.R.; da Costa Ferreira, A.M. Double-strand DNA cleavage induced by oxindole-Schiff base copper(II) complexes with potential antitumor activity. J. Inorg. Biochem., 2008, 102(5-6), 1090-1103.
[http://dx.doi.org/10.1016/j.jinorgbio.2007.12.033] [PMID: 18295339]
[55]
Siddiqi, Z.A.; Khalid, M.; Kumar, S.; Shahid, M.; Noor, S. Antimicrobial and SOD activities of novel transition metal complexes of pyri-dine-2,6-dicarboxylic acid containing 4-picoline as auxiliary ligand. Eur. J. Med. Chem., 2010, 45(1), 264-269.
[http://dx.doi.org/10.1016/j.ejmech.2009.10.005] [PMID: 19897283]
[56]
Papakonstantinou, V.D.; Lagopati, N.; Tsilibary, E.C.; Demopoulos, C.A.; Philippopoulos, A.I. A review on platelet acti-vating factor in-hibitors: could a new class of potent metal-based anti-inflammatory drugs induce anticancer properties? Bioinorg. Chem. Appl., 2017, 20176947034
[http://dx.doi.org/10.1155/2017/6947034] [PMID: 28458618]
[57]
Baker, C.J.; Smith, S.A.; Morrissey, J.H. Polyphosphate in thrombosis, hemostasis, and inflammation. Res. Pract. Thromb. Haemost., 2018, 3, 18-25.
[http://dx.doi.org/10.1182/blood-2012-07-444935] [PMID: 22968458]
[58]
Weitz, J.I.; Fredenburgh, J.C. Factor XI as a target for new antico-agulants. Arterioscler. Thromb. Vasc. Biol., 2018, 38(2), 304-310.
[http://dx.doi.org/10.1161/ATVBAHA.117.309664] [PMID: 29269514]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy