Structural and solution chemistry, antiproliferative effects, and serum albumin binding of three pseudohalide derivatives of auranofin

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Abstract

Three pseudohalide analogues of the established gold drug auranofin (AF hereafter), of general formula Au(PEt3)X, i.e. Au(PEt3)CN, Au(PEt3)SCN and Au(PEt3)N3 (respectively denoted as AFCN, AFSCN and AFN3), were prepared and characterized. The crystal structure was solved for Au(PEt3)SCN highlighting the classical linear geometry of the 2-coordinate gold(I) center. The solution behaviour of the compounds was then comparatively analysed through 31PNMR providing evidence for an acceptable stability under physiological-like conditions. Afterward, the reaction of these gold compounds with bovine serum albumin (BSA) and consequent adduct formation was investigated by 31PNMR. For all the studied gold compounds, the [Au(PEt3)]+ moiety was identified as the reactive species in metal/protein adducts formation. The cytotoxic effects of the complexes were subsequently measured in comparison to AF against a representative colorectal cancer cell line and found to be still relevant and roughly similar in the three cases though far weaker than those of AF. These results show that the nature of the anionic ligand can modulate importantly the pharmacological action of the gold-triethylphosphine moiety, affecting the cytotoxic potency. These aspects may be further explored to improve the pharmacological profiles of this family of metal complexes.

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Change history

  • 19 November 2019

    In the initial online publication, the given name of the first author was incorrectly displayed and should have read Damiano. The original article has been corrected and the proper representation of the authors’ names and their affiliation is also listed here.

References

  1. Allen FH (2002) The Cambridge structural database: a quarter of a million crystal structures and rising. Acta Crystallogr B58:380–388

    CAS  Article  Google Scholar 

  2. Altomare A, Burla MC, Camalli M, Cascarano GL, Giacovazzo C, Guagliardi A, Moliterni AGG, Polidori G, Spagna R (1999) SIR97: a new tool for crystal structure determination and refinement. J Appl Crystallogr 32:115–119

    CAS  Article  Google Scholar 

  3. Blocka KLN, Paulus HE, Furst DE (1986) Clinical pharmacokinetics of oral and injectable gold compounds. Clin Pharmacokinet 11:133–143

    CAS  Article  Google Scholar 

  4. Cirri D, Pillozzi S, Gabbiani C, Tricomi J, Bartoli G, Stefanini M, Michelucci E, Arcangeli A, Messori L, Marzo T (2017) PtI2(DACH), the iodido analogue of oxaliplatin as a candidate for colorectal cancer treatment: chemical and biological features. Dalton Trans 46:3311–3317

    CAS  Article  Google Scholar 

  5. Coffer MT, Shaw CF III, Eidsness MK, Watkins JW II, Elder RC (1986) Reactions of auranofin and chloro(triethylphosphine)gold with bovine serum albumin. Inorg Chem 25:333–339

    Article  Google Scholar 

  6. Coffer MT, Shaw CF III, Hormann AL, Mirabelli CK, Crooke ST (1987) Thiol competition for Et3PAuS-albumin: a nonenzymatic mechanism for Et3PO formation. J Inorg Biochem 30:177–187

    CAS  Article  Google Scholar 

  7. CrysAlisPro 1.171.38.41r, (2015) Rigaku Oxford Diffraction

  8. Database of privately and publicly funded clinical studies conducted around the world. https://clinicaltrials.gov

  9. El-Etri MM, Scovell WM (1990) Synthesis and spectroscopic characterization of (triethylphosphine)gold(I) complexes AuX(PEt3) (X = Cl, Br, CN, SCN), [AuL(PEt3)+] (L = SMe2, SC(NH2)2, H2O), and (μ-S)[Au(PEt3)]2. Inorg Chem 29:480–484

    CAS  Article  Google Scholar 

  10. Fabbrini MG, Cirri D, Pratesi A, Ciofi L, Marzo T, Guerri A, Nistri S, Dell’Accio A, Gamberi T, Severi M, Bencini A, Messori L (2019) A fluorescent silver(I) carbene complex with anticancer properties: synthesis, characterization, and biological studies. Chem Med Chem 14:182–188

    CAS  PubMed  Google Scholar 

  11. Fanali G, di Masi A, Trezza V, Marino M, Fasano M, Ascenzi P (2012) Human serum albumin: from bench to bedside. Mol Aspects Med 33:209–290

    CAS  Article  Google Scholar 

  12. Farrugia LJ (1997) ORTEP-3 for Windows—a version of ORTEP-III with a Graphical User Interface (GUI). J Appl Crystallogr 30:565

    CAS  Article  Google Scholar 

  13. Farrugia LJ (2012) WinGX and ORTEP for Windows: an update. J Appl Crystallogr 45:849–854

    CAS  Article  Google Scholar 

  14. Hormann-Arendt AL, Shaw CF III (1990) Ligand-scrambling reactions of cyano(trialkyl/triarylphosphine)gold(I) complexes: examination of factors influencing the equilibrium constant. Inorg Chem 29:4683–4687

    CAS  Article  Google Scholar 

  15. Hou GX, Liu PP, Zhang S, Yang M, Liao J, Yang J, Hu Y, Jiang WQ, Wen S, Huang P (2018) Elimination of stem-like cancer cell side-population by auranofin through modulation of ROS and glycolysis. Cell Death Dis 9:89–103

    Article  Google Scholar 

  16. Isab AA, Hormann AL, Coffer MT, Shaw CF III (1988a) Reversibly and irreversibly formed products from the reactions of mercaptalbumin (AlbSH) with Et3PAuCN and of AlbSAuPEt3 with HCN. J Am Chem Soc 110:3278–3284

    CAS  Article  Google Scholar 

  17. Isab AA, Shaw CF III, Hoeschele JD, Locke J (1988b) Reactions of trimethylphosphine analogs of auranofin with bovine serum albumin. Inorg Chem 27:3588–3592

    CAS  Article  Google Scholar 

  18. Landini I, Lapucci A, Pratesi A, Massai L, Napoli C, Perrone G, Pinzani P, Messori L, Mini E, Nobili S (2017) Selection and characterization of a human ovarian cancer cell line resistant to auranofin. Oncotarget 8:96062–96078

    Article  Google Scholar 

  19. Lee P, Wu X (2015) Review: modifications of human serum albumin and their binding effect. Curr Pharm Des 21:1862–1865

    CAS  Article  Google Scholar 

  20. Marcon G, Messori L, Orioli P, Cinellu MA, Minghetti G (2003) Reactions of gold(III) complexes with serum albumin. Eur J Biochem 270:4655–4661

    CAS  Article  Google Scholar 

  21. Marzo T, Cirri D, Gabbiani C, Gamberi T, Magherini F, Pratesi A, Guerri A, Biver T, Binacchi F, Stefanini M, Arcangeli A, Messori L (2017) Auranofin, Et3PAuCl, and Et3PAuI are highly cytotoxic on colorectal cancer cells: a chemical and biological study. ACS Med Chem Lett 8:997–1001

    CAS  Article  Google Scholar 

  22. Marzo T, Cirri D, Pollini S, Prato M, Fallani S, Cassetta MI, Novelli A, Rossolini GM, Messori L (2018) Auranofin and its analogues show potent antimicrobial activity against multidrug-resistant pathogens: structure–activity relationships. ChemMedChem 13:2448–2454

    CAS  Article  Google Scholar 

  23. Marzo T, Massai L, Pratesi A, Stefanini M, Cirri D, Magherini F, Becatti M, Landini I, Nobili S, Mini E, Crociani O, Arcangeli A, Pillozzi S, Gamberi T, Messori L (2019) Replacement of the thiosugar of auranofin with iodide enhances the anticancer potency in a mouse model of ovarian cancer. ACS Med Chem Lett 10:656–660

    CAS  Article  Google Scholar 

  24. Massai L, Pratesi A, Gailer J, Marzo T, Messori L (2019) The cisplatin/serum albumin system: a reappraisal. Inorg Chim Acta 495:118983–118989

    CAS  Article  Google Scholar 

  25. May HC, Yu JJ, Guentzel MN, Chambers JP, Cap AP, Arulanandam BP (2018) Repurposing Auranofin, Ebselen, and PX-12 as antimicrobial agents targeting the thioredoxin system. Front Microbiol 9:336–345

    Article  Google Scholar 

  26. Nardelli M (1995) PARST95—an update to PARST: a system of Fortran routines for calculating molecular structure parameters from the results of crystal structure analyses. J Appl Crystallogr 28:659

    CAS  Article  Google Scholar 

  27. Pratesi A, Cirri D, Ciofi L, Messori L (2018) Reactions of auranofin and its pseudohalide derivatives with serum albumin investigated through ESI-Q-TOF MS. Inorg Chem 57:10507–10510

    CAS  Article  Google Scholar 

  28. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18:41–58

    CAS  Article  Google Scholar 

  29. Roder C, Thomson MJ (2015) Auranofin: repurposing an old drug for a golden new age. Drugs R D 15:13–20

    CAS  Article  Google Scholar 

  30. Singh N, Pagariya D, Jain S, Naik S, Kishore N (2018) Interaction of copper (II) complexes by bovine serum albumin: spectroscopic and calorimetric insights. J Biomol Struct Dyn 9:2449–2462

    Article  Google Scholar 

  31. Sokołowska M, Wszelaka-Rylik M, Poznański J, Bal W (2009) Spectroscopic and thermodynamic determination of three distinct binding sites for Co(II) ions in human serum albumin. J Inorg Biochem 103:1005–1013

    Article  Google Scholar 

  32. Talib J, Beck JL, Ralph SF (2006) A mass spectrometric investigation of the binding of gold antiarthritic agents and the metabolite [Au(CN)2] to human serum albumin. J Biol Inorg Chem 11:559–570

    CAS  Article  Google Scholar 

  33. Thorn A, Dittrich B, Sheldrick GM (2012) Enhanced rigid-bond restraints. Acta Crystallogr A68:448–451

    Article  Google Scholar 

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Acknowledgements

D.C. gratefully acknowledge Associazione Italiana per la Ricerca sul Cancro for the financial support (AIRC 1-year Fellowship for Italy—Project Code: 22294). L.M. gratefully acknowledges AIRC (Associazione Italiana per la Ricerca sul Cancro) and ECRF (Ente Cassa di Risparmio di Firenze) for the financial support (AIRC-ECRF19650). CIRCMSB and ente CRF are also acknowledged. T.M. thanks University of Pisa (Rating Ateneo 2018/2019) for the financial support.

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The original version of this article was revised: the given name of the first author has been corrected.

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Cirri, D., Fabbrini, M.G., Massai, L. et al. Structural and solution chemistry, antiproliferative effects, and serum albumin binding of three pseudohalide derivatives of auranofin. Biometals 32, 939–948 (2019). https://doi.org/10.1007/s10534-019-00224-1

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Keywords

  • Metal based drugs
  • NMR
  • Cancer
  • Protein metalation
  • BSA