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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Allen FH (2002) The Cambridge structural database: a quarter of a million crystal structures and rising. Acta Crystallogr B58:380–388
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
Blocka KLN, Paulus HE, Furst DE (1986) Clinical pharmacokinetics of oral and injectable gold compounds. Clin Pharmacokinet 11:133–143
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
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
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
CrysAlisPro 22.214.171.124r, (2015) Rigaku Oxford Diffraction
Database of privately and publicly funded clinical studies conducted around the world. https://clinicaltrials.gov
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
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
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
Farrugia LJ (1997) ORTEP-3 for Windows—a version of ORTEP-III with a Graphical User Interface (GUI). J Appl Crystallogr 30:565
Farrugia LJ (2012) WinGX and ORTEP for Windows: an update. J Appl Crystallogr 45:849–854
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
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
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
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
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
Lee P, Wu X (2015) Review: modifications of human serum albumin and their binding effect. Curr Pharm Des 21:1862–1865
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
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
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
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
Massai L, Pratesi A, Gailer J, Marzo T, Messori L (2019) The cisplatin/serum albumin system: a reappraisal. Inorg Chim Acta 495:118983–118989
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
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
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
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
Roder C, Thomson MJ (2015) Auranofin: repurposing an old drug for a golden new age. Drugs R D 15:13–20
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
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
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
Thorn A, Dittrich B, Sheldrick GM (2012) Enhanced rigid-bond restraints. Acta Crystallogr A68:448–451
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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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
- Metal based drugs
- Protein metalation