Abstract
A set of dinuclear copper(I) complexes with the general formula [Cu2(μ-dppm)2(N^N)2]2+ were synthesized and characterized by 1HNMR, 31PNMR, and elemental analysis. The high-resolution mass spectra clearly illustrated isotopic pattern for the proposed dinuclear systems. The binding of the complexes toward human serum albumin (HSA) were evaluated, highlighting good binding affinities influenced by the nature of the substituted-diimine. The complexes induce changes in both the α-helix and the microenvironment structures of HSA. The HSA-bindings were modelled by molecular docking; [Cu2(μ-dppm)2(dppz)2][ClO4]2 (3) displays the highest binding score toward HSA due to the ability of dppz in establishing π-interactions. The anticancer properties of 1, 2 and 3 were screened against COLO 205, RCC-PR, HepGII and LLC-MK2 cell lines and the results were discussed. Complex 3 has better IC50 against all the cancer cell lines than that observed for cisplatin, but still lower than the cytotoxicity of Sunitinib. Moreover, complex 3 has higher selectivity towards cancer cells over normal cells when compared to cisplatin and sunitinib.
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Abbreviations
- HAS:
-
Human serum albumin
- COLO-205:
-
Human colon carcinoma
- RCC-PR:
-
Human kidney clear cell carcinoma
- HepGII:
-
Liver hepatocellular carcinoma
- LLC-MK2:
-
Rhesus monkey kidney epithelial normal cells
References
B. Babgi, Synthetic protocols and applications of copper(I) phosphine and copper(I) phosphine/diimine complexes. J. Organomet. Chem. 956, 122124 (2021)
G. Mani, V. Subramaniyan, Chapter 8 - Homoleptic and heteroleptic copper(I) complexes bearing diimine-diphosphine ligands, in Copper(I) Chemistry of Phosphines, Functionalized Phosphines and Phosphorus Heterocycles. ed. by M.S. Balakrishna (Elsevier, Amsterdam, 2019), pp. 237–258
F. Tisato, M. Porchia, C. Santini, V. Gandin, C. Marzano, Chapter 3 - Phosphine–copper(I) complexes as anticancer agents: design, synthesis, and physicochemical characterization. Part I, in Copper(I) Chemistry of Phosphines, Functionalized Phosphines and Phosphorus Heterocycles. ed. by M.S. Balakrishna (Elsevier, Amsterdam, 2019), pp. 61–82
C. Marzano, F. Tisato, M. Porchia, M. Pellei, V. Gandin, Chapter 4 - Phosphine copper(I) complexes as anticancer agents: biological characterization. Part II, in Copper(I) Chemistry of Phosphines, Functionalized Phosphines and Phosphorus Heterocycles. ed. by M.S. Balakrishna (Elsevier, Amsterdam, 2019), pp. 83–107
L. Colina-Vegas, W. Villarreal, M. Navarro, Chapter 5 - Copper(I)–phosphine complexes: a promising approach in the search for antitumor agents, in Copper(I) Chemistry of Phosphines, Functionalized Phosphines and Phosphorus Heterocycles. ed. by M.S. Balakrishna (Elsevier, Amsterdam, 2019), pp. 109–143
E. Wong, C.M. Giandomenico, Current status of platinum-based antitumor drugs. Chem. Rev. 99, 2451–2466 (1999)
A.S. Abu-Surrah, M. Kettunen, Platinum group antitumor chemistry: design and development of new anticancer drugs complementary to cisplatin. Curr. Med. Chem. 13, 1337–1357 (2006)
C.A. Rabik, M.E. Dolan, Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat. Rev. 33, 9–23 (2007)
R. Starosta, K. Stokowa, M. Florek, J. Król, A. Chwiłkowska, J. Kulbacka, J. Saczko, J. Skała, M. Jeżowska-Bojczuk, Biological activity and structure dependent properties of cuprous iodide complexes with phenanthrolines and water soluble tris (aminomethyl) phosphanes. J. Inorg. Biochem. 105, 1102–1108 (2011)
K.H. Mashat, B.A. Babgi, M.A. Hussien, M.N. Arshad, M.H. Abdellattif, Synthesis, structures, DNA-binding and anticancer activities of some copper (I)-phosphine complexes. Polyhedron 158, 164–172 (2019)
B.A. Babgi, K.H. Mashat, M.H. Abdellattif, M.N. Arshad, K.A. Alzahrani, A.M. Asiri, J. Du, M.G. Humphrey, M.A. Hussien, Synthesis, structures, DNA-binding, cytotoxicity and molecular docking of CuBr (PPh3)(diimine). Polyhedron 192, 114847 (2020)
S. Alsaedi, B.A. Babgi, M.H. Abdellattif, M.N. Arshad, A.-H.M. Emwas, M. Jaremko, M.G. Humphrey, A.M. Asiri, M.A. Hussien, DNA-binding and cytotoxicity of copper (I) complexes containing functionalized dipyridylphenazine ligands. Pharmaceutics 13, 764 (2021)
J. Fernandez-Gallardo, B.T. Elie, M. Sanaú, M. Contel, Versatile synthesis of cationic N-heterocyclic carbenee gold(I) complexes containing a second ancillary ligand. Design of heterobimetallic rutheniumegold anticancer agents. Chem. Commun. 52, 3155–3158 (2016)
L. Massai, J. Fernandez-Gallardo, A. Guerri, A. Arcangeli, S. Pillozzi, M. Contel, L. Messori, Design, synthesis and characterisation of new chimeric ruthenium(II)-gold(I) complexes as improved cytotoxic agents. Dalton Trans. 44, 11067–11076 (2015)
M. Odachowski, C. Marschner, B. Blom, A review on 1, 1-bis (diphenylphosphino) methane bridged homo-and heterobimetallic complexes for anticancer applications: Synthesis, structure, and cytotoxicity. Eur. J. Med. Chem. 2020, 112613 (2020)
M.S. Alsaeedi, B.A. Babgi, M.A. Hussien, M.H. Abdellattif, M.G. Humphrey, DNA-binding and anticancer activity of binuclear gold(I) alkynyl complexes with a phenanthrenyl bridging ligand. Molecules 25, 1033 (2020)
G.B. Jacobsen, B.L. Shaw, M. Thornton-Pett, Rhodium(I)-iron(0) carbonyl complexes containing one bridging Ph2PCH2PPh2 ligand, including the formation of a tetranuclear cluster from a heterobimetallic precursor: crystal structures of [(OC)4Fe(μ-Ph2PCH2PPh2)RhCl(CO)] and [Fe2Rh2(μ-Ph2PCH2PPh2)2(CO)8]. J. Chem. Soc. Dalton Trans. 11, 2751–2755 (1987)
C. Lecomte, S. Skoulika, P. Aslanidis, P. Karagiannidis, S. Papastefanou, Copper(I) bromide complexes with heterocyclic thiones and triphenylphosphine as ligands. The X-ray crystal structure of copper(I) pyrimidine-2-thione bis (triphenylphosphine) bromide [Cu(PPh3)2(PymtH)Br]. Polyhedron 8, 1103–1109 (1989)
I. Ascone, L. Messori, A. Casini, C. Gabbiani, A. Balerna, F. Dell’Unto, A.C. Castellano, Exploiting soft and hard X-ray absorption spectroscopy to characterize metallodrug/protein interactions: the binding of [trans-RuCl4(Im)(dimethylsulfoxide)][ImH] (Im = imidazole) to bovine serum albumin. Inorg. Chem. 47, 8629–8634 (2008)
M. Groessl, M. Terenghi, A. Casini, L. Elviri, R. Lobinski, P.J. Dyson, Reactivity of anticancer metallodrugs with serum proteins: new insights from size exclusion chromatography-ICP-MS and ESI-MS. J. Anal. At. Spectrom. 25, 305–313 (2010)
A.Y. Shmykov, V.N. Filippov, L.S. Foteeva, B.K. Keppler, A.R. Timerbaev, Toward high-throughput monitoring of metallodrug–protein interaction using capillary electrophoresis in chemically modified capillaries. Anal. Biochem. 379, 216–218 (2008)
A.R. Timerbaev, C.G. Hartinger, S.S. Aleksenko, B.K. Keppler, Interactions of antitumor metallodrugs with serum proteins: advances in characterization using modern analytical methodology. Chem. Rev. 106, 2224–2248 (2006)
D. Gibellini, F. Vitone, P. Schiavone, C. Ponti, M.L. Placa, M.C. Re, Quantitative detection of human immunodeficiency virus type 1 (HIV-1) proviral DNA in peripheral blood mononuclear cells by SYBR green real-time PCR technique. J. Clin. Virol. 29, 282 (2004)
J.R. Lakowicz, Principles of Fluorescence Spectroscopy, 3rd edn. (Springer, New York, 2006)
M.-M. Wu, L.-Y. Zhang, Y.-H. Qin, Z.-N. Chen, Bis[μ-bis(diphenylphosphino)methane-κ2P:P′]bis[diacetonitrilecopper(I)] bis(hexafluorophosphate). Acta Cryst. Sect. E 59, m195–m196 (2003)
B.A. Babgi, J.H. Alsayari, B. Davaasuren, A.-H.M. Emwas, M. Jaremko, M.H. Abdellattif, M.A. Hussien, Synthesis, structural studies and anticancer properties of the [CuBr(PPh3)2(4,6-dimethyl-2-thiopyrimidine-κS]. Crystals 11, 688 (2021)
S. Nafisi, G.B. Sadeghi, A. PanahYab, Interaction of aspirin and vitamin C with bovine serum albumin. J. Photochem. Photobiol. B: Biol. 105, 198–202 (2011)
B.K. Hoefelschweiger, A. Duerkop, O.S. Wolfbeis, Novel type of general protein assay using a chromogenic and fluorogenic amine-reactive probe. Anal. Biochem. 344, 122–129 (2005)
I. Petitpas, A.A. Bhattacharya, S. Twine, M. East, S. Curryi, Crystal structure analysis of warfarin binding to human serum albumin: anatomy of drug site I. J. Biol. Chem. 276, 22804–22809 (2001)
N.D. Al-Khathami, K.S. Al-Rashdi, B.A. Babgi, M.A. Hussien, M.N. Arshad, N.E. Eltayeb, S.E. Elsilk, J. Lasri, A.S. Basaleh, M. Al-Jahdali, Spectroscopic and biological properties of platinum complexes derived from 2-pyridyl Schiff bases. J. Saudi Chem. Soc. 23, 903–915 (2019)
M.H. Abdel-Rhman, M.A. Hussien, H.M. Mahmoud, N.M. Hosny, Synthesis, characterization, molecular docking and cytotoxicity studies on N-benzyl-2-isonicotinoylhydrazine-1-carbothioamide and its metal complexes. J. Mol. Struct. 1196, 417–428 (2019)
J.C. Cole, C.W. Murray, J.W. Nissink, R.D. Taylor, R. Taylor, Comparing protein-ligand docking programs is difficult. Proteins 60, 325–332 (2005)
N. Muanza, B.W. Kim, K.L. Euler, L. Williams, Antibacterial and antifungal activities of nine medicinal plants from Zaire. Int. J. Pharmacogn. 32, 337–345 (1994)
J.M. Pezzuto, C.-T. Che, D.D. McPherson, J.-P. Zhu, G. Topcu, C.A.J. Erdelmeier, G.A. Cordell, DNA as an affinity probe useful in the detection and isolation of biologically active natural products. J. Nat. Prod. 54, 1522–1530 (1991)
P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J. Warren, H. Bokesch, S. Kenney, M. Boyd, New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 1107–1112 (1990)
A. Kaeser, M. Mohankumar, J. Mohanraj, F. Monti, M. Holler, J.-J. Cid, O. Moudam, I. Nierengarten, L. Karmazin-Brelot, C. Duhayon, B. Delavaux-Nicot, N. Armaroli, J.-F. Nierengarten, Heteroleptic copper(I) complexes prepared from phenanthroline and bis-phosphine ligands. Inorg. Chem. 52, 12140–12151 (2013)
S. Roy, T.K. Mondal, P. Mitra, C. Sinha, Copper(I)/silver(I)-phosphine-N-{(2-pyridyl)methyliden}-6-coumarin complexes: syntheses, structures, redox interconversion, photophysical properties and DFT computation. Polyhedron 51, 27–40 (2013)
S. Al-Harthi, J.I. Lachowicz, M.E. Nowakowski, M. Jaremko, Ł Jaremko, Towards the functional high-resolution coordination chemistry of blood plasma human serum albumin. J. Inorg. Biochem. 198, 110716 (2019)
M.K. Helms, C.E. Petersen, N.V. Bhagavan, D.M. Jameson, Time-resolved fluorescence studies on site-directed mutants of human serum albumin. FEBS Lett. 408, 67–70 (1997)
M. El-Kemary, M. Gil, A. Douhal, Relaxation dynamics of piroxicam structures within human serum albumin protein. J. Med. Chem. 50, 2896–2902 (2007)
X.M. He, D.C. Carter, Atomic structure and chemistry of human serum albumin. Nature 358, 209–215 (1992)
V. Lhiaubet-Vallet, Z. Sarabia, F. Boscá, M.A. Miranda, Human serum albumin-mediated stereodifferentiation in the triplet state behavior of (S)- and (R)-carprofen. J. Am. Chem. Soc. 126, 9538–9539 (2004)
D.P. Yeggoni, M. Gokara, D.M. Manidhar, A. Rachamallu, S. Nakka, C.S. Reddy, R. Subramanyam, Binding and molecular dynamics studies of 7-hydroxycoumarin derivatives with human serum albumin and its pharmacological importance. Mol. Pharm. 11, 1117–1131 (2014)
O. Exner, Calculating equilibrium constants from spectral data: reliability of the Benesi-Hildebrand method and its modifications. Chemomet. Intell. Lab. Syst. 39, 85–93 (1997)
N. Shahabadi, S. Kashanian, K. Shalmashi, H. Roshanfekr, DNA interaction with PtCl2(LL) (LL = chelating diamine ligand: N, N-dimethyltrimethylendiamine) complex. Appl. Biochem. Biotechnol. 158, 1–10 (2009)
B. Bhattacharya, S. Nakka, L. Guruprasad, A. Samanta, Interaction of bovine serum albumin with dipolar molecules: fluorescence and molecular docking studies. J. Phys. Chem. B 113, 2143–2150 (2009)
S. Dasari, P.B. Tchounwou, Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharm. 740, 364–378 (2014)
V.L. Goodman, E.P. Rock, R. Dagher, R.P. Ramchandani, S. Abraham, J.V.S. Gobburu, B.P. Booth, S.L. Verbois, D.E. Morse, C.Y. Liang, N. Chidambaram, J.X. Jiang, S. Tang, K. Mahjoob, R. Justice, R. Pazdur, Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 13, 1367–1373 (2007)
B.A. Babgi, D. Domyati, M.H. Abdellattif, M.A. Hussien, Evaluation of the anticancer and DNA-binding characteristics of dichloro (diimine) zinc (II) complexes. Chemistry 3, 1178–1188 (2021)
R.J. Motzer, B. Escudier, A. Gannon, R.A. Figlin, Sunitinib: ten years of successful clinical use and study in advanced renal cell carcinoma. Oncologist 22, 41–52 (2017)
Acknowledgements
This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia under grant no. (G-1436-130-43). The authors, therefore, acknowledge with thanks DSR technical and financial support.
Funding
This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia under Grant No. (G-1436-130-43). The authors, therefore, acknowledge with thanks DSR technical and financial support.
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Conceptualization, BAB; Data curation, NAA and JHA; Formal analysis, JHA, MHA, A-HME and MJ; Funding acquisition, BAB; Investigation, BAB and NAA; Methodology, A-HME; Project administration, BAB; Resources, MJ and BAB; Software, MHA and MAH; Supervision, BAB; Visualization, MAH; Writing–original draft, BAB; Writing–review & editing, BAB and MA.
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Babgi, B.A., Alzaidi, N.A., Alsayari, J.H. et al. Synthesis, HSA-Binding and Anticancer Properties of [Cu2(\(\mu\)-dppm)2(N^N)2]2+. J Inorg Organomet Polym 32, 4005–4013 (2022). https://doi.org/10.1007/s10904-022-02404-y
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DOI: https://doi.org/10.1007/s10904-022-02404-y