Skip to main content
SpringerLink
Log in

Synthesis, characterization, and biological activity of cationic ruthenium–arene complexes with sulfur ligands

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

Five cationic ruthenium–arene complexes with the generic formula [Ru(SAc)(S2C·NHC)(p-cymene)](PF6) (5a–e) were prepared in almost quantitative yields using a straightforward one-pot, two-step experimental procedure starting from [RuCl2(p-cymene)]2, an imidazol(in)ium-2-dithiocarboxylate (NHC·CS2) zwitterion, KSAc, and KPF6. These half-sandwich compounds were fully characterized by various analytical techniques and the molecular structures of two of them were solved by X-ray diffraction analysis, which revealed the existence of an intramolecular chalcogen bond between the oxygen atom of the thioacetate ligand and a proximal sulfur atom of the dithiocarboxylate unit. DFT calculations showed that the C=S…O charge transfer amounted to 2.4 kcal mol−1. The dissolution of [Ru(SAc)(S2C·IMes)(p-cymene)](PF6) (5a) in moist DMSO-d6 at room temperature did not cause the dissociation of its sulfur ligands. Instead, p-cymene was slowly released to afford the 12-electron [Ru(SAc)(S2C·IMes)]+ cation that could be detected by mass spectrometry. Monitoring the solvolysis process by 1H NMR spectroscopy showed that more than 22 days were needed to fully decompose the starting ruthenium–arene complex. Compounds 5a–e exhibited a high antiproliferative activity against human glioma Hs683 and human lung carcinoma A549 cancer cells. In particular, the IMes derivative (5a) was the most potent compound of the series, achieving toxicities similar to those displayed by marketed platinum drugs.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4
Fig. 5
Scheme 2
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

The data supporting the findings of this study are available within the published article and its Supplementary Information files.

References

  1. Collier WA, Krauss F (1931) Zur experimentellen Therapie der Tumoren. Z Krebsforsch 34:526–530. https://doi.org/10.1007/bf01625394

    Article  CAS  Google Scholar 

  2. Dwyer FP, Gyarfas EC, Rogers WP, Koch JH (1952) Biological activity of complex ions. Nature 170:190–191. https://doi.org/10.1038/170190a0

    Article  CAS  PubMed  Google Scholar 

  3. Süss-Fink G (2010) Arene ruthenium complexes as anticancer agents. Dalton Trans 39:1673–1688. https://doi.org/10.1039/b916860p

    Article  CAS  PubMed  Google Scholar 

  4. Ang WH, Casini A, Sava G, Dyson PJ (2011) Organometallic ruthenium-based antitumor compounds with novel modes of action. J Organomet Chem 696:989–998. https://doi.org/10.1016/j.jorganchem.2010.11.009

    Article  CAS  Google Scholar 

  5. Noffke AL, Habtemariam A, Pizarro AM, Sadler PJ (2012) Designing organometallic compounds for catalysis and therapy. Chem Commun 48:5219–5246. https://doi.org/10.1039/c2cc30678f

    Article  CAS  Google Scholar 

  6. Nazarov AA, Hartinger CG, Dyson PJ (2014) Opening the lid on piano-stool complexes: an account of ruthenium(II)–arene complexes with medicinal applications. J Organomet Chem 751:251–260. https://doi.org/10.1016/j.jorganchem.2013.09.016

    Article  CAS  Google Scholar 

  7. Singh SK, Pandey DS (2014) Multifaceted half-sandwich arene-ruthenium complexes: interactions with biomolecules, photoactivation, and multinuclearity approach. RSC Adv 4:1819–1840. https://doi.org/10.1039/c3ra44131h

    Article  CAS  Google Scholar 

  8. Blunden BM, Stenzel MH (2015) Incorporating ruthenium into advanced drug delivery carriers—an innovative generation of chemotherapeutics. J Chem Technol Biotechnol 90:1177–1195. https://doi.org/10.1002/jctb.4507

    Article  CAS  Google Scholar 

  9. Mari C, Pierroz V, Ferrari S, Gasser G (2015) Combination of Ru(II) complexes and light: new frontiers in cancer therapy. Chem Sci 6:2660–2686. https://doi.org/10.1039/c4sc03759f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Murray BS, Babak MV, Hartinger CG, Dyson PJ (2016) The development of RAPTA compounds for the treatment of tumors. Coord Chem Rev 306:86–114. https://doi.org/10.1016/j.ccr.2015.06.014

    Article  CAS  Google Scholar 

  11. Thota S, Rodrigues DA, Crans DC, Barreiro EJ (2018) Ru(II) compounds: next-generation anticancer metallotherapeutics? J Med Chem 61:5805–5821. https://doi.org/10.1021/acs.jmedchem.7b01689

    Article  CAS  PubMed  Google Scholar 

  12. Meier-Menches SM, Gerner C, Berger W, Hartinger CG, Keppler BK (2018) Structure–activity relationships for ruthenium and osmium anticancer agents—towards clinical development. Chem Soc Rev 47:909–928. https://doi.org/10.1039/c7cs00332c

    Article  CAS  PubMed  Google Scholar 

  13. Marchetti F, Pettinari R, Di Nicola C, Pettinari C, Palmucci J, Scopelliti R, Riedel T, Therrien B, Galindo A, Dyson PJ (2018) Synthesis, characterization and cytotoxicity of arene–ruthenium(II) complexes with acylpyrazolones functionalized with aromatic groups in the acyl moiety. Dalton Trans 47:868–878. https://doi.org/10.1039/c7dt04249c

    Article  CAS  PubMed  Google Scholar 

  14. Swaminathan S, Haribabu J, Kalagatur NK, Konakanchi R, Balakrishnan N, Bhuvanesh N, Karvembu R (2019) Synthesis and anticancer activity of [RuCl2(η6-arene)(aroylthiourea)] complexes—high activity against the human neuroblastoma (IMR-32) cancer cell line. ACS Omega 4:6245–6256. https://doi.org/10.1021/acsomega.9b00349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Khan TA, Bhar K, Thirumoorthi R, Roy TK, Sharma AK (2020) Design, synthesis, characterization and evaluation of the anticancer activity of water-soluble half-sandwich ruthenium(II) arene halido complexes. New J Chem 44:239–257. https://doi.org/10.1039/c9nj03663f

    Article  CAS  Google Scholar 

  16. Chen C, Xu C, Li T, Lu S, Luo F, Wang H (2020) Novel NHC-coordinated ruthenium(II) arene complexes achieve synergistic efficacy as safe and effective anticancer therapeutics. Eur J Med Chem 203:112605. https://doi.org/10.1016/j.ejmech.2020.112605

    Article  CAS  PubMed  Google Scholar 

  17. Harringer S, Wernitznig D, Gajic N, Diridl A, Wenisch D, Hejl M, Jakupec MA, Theiner S, Koellensperger G, Kandioller W, Keppler BK (2020) Introducing N-, P-, and S-donor leaving groups: an investigation of the chemical and biological properties of ruthenium, rhodium and iridium thiopyridone piano stool complexes. Dalton Trans 49:15693–15711. https://doi.org/10.1039/d0dt03165h

    Article  CAS  PubMed  Google Scholar 

  18. Marloye M, Inam H, Moore CJ, Debaille V, Pritchard JR, Gelbcke M, Meyer F, Dufrasne F, Berger G (2021) Synthesis, structure and anticancer properties of new biotin- and morpholine-functionalized ruthenium and osmium half-sandwich complexes. J Biol Inorg Chem 26:535–549. https://doi.org/10.1007/s00775-021-01873-9

    Article  CAS  PubMed  Google Scholar 

  19. Rafols L, Josa D, Aguilà D, Barrios L, Roubeau O, Cirera J, Soto-Cerrato V, Pérez-Tomás R, Martínez M, Grabulosa A, Gamez P (2021) Piano-stool ruthenium(II) complexes with delayed cytotoxic activity: origin of the lag time. Inorg Chem 60:7974–7990. https://doi.org/10.1021/acs.inorgchem.1c00507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Delaude L, Sauvage X, Demonceau A, Wouters J (2009) Synthesis and catalytic evaluation of ruthenium-arene complexes generated using imidazol(in)ium-2-carboxylates and -dithiocarboxylates. Organometallics 28:4056–4064. https://doi.org/10.1021/om9002363

    Article  CAS  Google Scholar 

  21. Willem Q, Nicks F, Sauvage X, Delaude L, Demonceau A (2009) Ruthenium–arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands: evaluation of their catalytic activity in the synthesis of enol esters. J Organomet Chem 694:4049–4055. https://doi.org/10.1016/j.jorganchem.2009.08.028

    Article  CAS  Google Scholar 

  22. Delaude L (2009) Betaine adducts of N-heterocyclic carbenes: synthesis, properties, and reactivity. Eur J Inorg Chem. https://doi.org/10.1002/ejic.200801227

  23. Beltrán TF, Delaude L (2017) Recent advances in small clusters and polymetallic assemblies based on transition metals and dithiocarboxylate zwitterions derived from N-heterocyclic carbenes. J Cluster Sci 28:667–678. https://doi.org/10.1007/s10876-017-1174-4

    Article  CAS  Google Scholar 

  24. Delaude L, Demonceau A, Wouters J (2009) Assessing the potentials of zwitterionic NHC·CS2 adducts for probing the stereoelectronic parameters of N-heterocyclic carbenes. Eur J Inorg Chem. https://doi.org/10.1002/ejic.200801110

  25. Mazars F, Hrubaru M, Tumanov N, Wouters J, Delaude L (2021) Synthesis of azolium-2-dithiocarboxylate zwitterions under mild, aerobic conditions. Eur J Org Chem. https://doi.org/10.1002/ejoc.202100274

  26. Zain Aldin M, Zaragoza G, Deschamps W, Tomani J-CD, Souopgui J, Delaude L (2021) Synthesis, characterization, and biological activity of water-soluble, dual anionic and cationic ruthenium-arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands. Inorg Chem 60:16769–16781. https://doi.org/10.1021/acs.inorgchem.1c02648

    Article  CAS  PubMed  Google Scholar 

  27. Wang F, Chen H, Parsons S, Oswald IDH, Davidson JE, Sadler PJ (2003) Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts. Chem Eur J 9:5810–5820. https://doi.org/10.1002/chem.200304724

    Article  CAS  PubMed  Google Scholar 

  28. Wang F, Habtemariam A, van der Geer EPL, Fernández R, Melchart M, Deeth RJ, Aird R, Guichard S, Fabbiani FPA, Lozano-Casal P, Oswald IDH, Jodrell DI, Parsons S, Sadler PJ (2005) Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity. Proc Natl Acad Sci USA 102:18269. https://doi.org/10.1073/pnas.0505798102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ang WH, Daldini E, Scolaro C, Scopelliti R, Juillerat-Jeannerat L, Dyson PJ (2006) Development of organometallic ruthenium-arene anticancer drugs that resist hydrolysis. Inorg Chem 45:9006–9013. https://doi.org/10.1021/ic061008y

    Article  CAS  PubMed  Google Scholar 

  30. Scolaro C, Hartinger CG, Allardyce CS, Keppler BK, Dyson PJ (2008) Hydrolysis study of the bifunctional antitumour compound RAPTA-C, [Ru(η6-p-cymene)Cl2(pta)]. J Inorg Biochem 102:1743–1748. https://doi.org/10.1016/j.jinorgbio.2008.05.004

    Article  CAS  PubMed  Google Scholar 

  31. Futera Z, Klenko J, Šponer JE, Šponer J, Burda JV (2009) Interactions of the “piano-stool” [ruthenium(II)(η6-arene)(en)Cl]+ complexes with water and nucleobases; ab initio and DFT study. J Comput Chem 30:1758–1770. https://doi.org/10.1002/jcc.21179

    Article  CAS  PubMed  Google Scholar 

  32. Zhao J, Zhang X, Liu H, Xiong Z, Li M, Chen T (2019) Ruthenium arene complex induces cell cycle arrest and apoptosis through activation of P53-mediated signaling pathways. J Organomet Chem 898:120869. https://doi.org/10.1016/j.jorganchem.2019.07.020

    Article  CAS  Google Scholar 

  33. Lovison D, Allegri L, Baldan F, Ballico M, Damante G, Jandl C, Baratta W (2020) Cationic carboxylate and thioacetate ruthenium(II) complexes: synthesis and cytotoxic activity against anaplastic thyroid cancer cells. Dalton Trans 49:8375–8388. https://doi.org/10.1039/d0dt01390k

    Article  CAS  PubMed  Google Scholar 

  34. Al-Buthabhak HS, Falasca V, Yu Y, Sobolev AN, Skelton BW, Moggach SA, Ferro V, Al-Salami H, Baker MV (2022) Au-NHC complexes with thiocarboxylate ligands: synthesis, structure, stability, thiol exchange and in vitro anticancer activity. Appl Organomet Chem. https://doi.org/10.1002/aoc.6645

  35. Furrer J, Süss-Fink G (2016) Thiolato-bridged dinuclear arene ruthenium complexes and their potential as anticancer drugs. Coord Chem Rev 309:36–50. https://doi.org/10.1016/j.ccr.2015.10.007

    Article  CAS  Google Scholar 

  36. Păunescu E, Boubaker G, Desiatkina O, Anghel N, Amdouni Y, Hemphill A, Furrer J (2021) The quest of the best—a SAR study of trithiolato-bridged dinuclear ruthenium(II)-arene compounds presenting antiparasitic properties. Eur J Med Chem 222:113610. https://doi.org/10.1016/j.ejmech.2021.113610

    Article  CAS  PubMed  Google Scholar 

  37. Desiatkina O, Anghel N, Boubaker G, Amdouni Y, Hemphill A, Furrer J, Păunescu E (2023) Trithiolato-bridged dinuclear ruthenium(II)-arene conjugates tethered with lipophilic units: synthesis and Toxoplasma gondii antiparasitic activity. J Organomet Chem 986:122624. https://doi.org/10.1016/j.jorganchem.2023.122624

    Article  CAS  Google Scholar 

  38. Bruker, (2005) APEX 3. Bruker AXS Inc., Madison

    Google Scholar 

  39. Clark RC, Reid JS (1995) The analytical calculation of absorption in multifaceted crystals. Acta Crystallogr Sect A Fundam Crystallogr 51:887–897. https://doi.org/10.1107/s0108767395007367

    Article  Google Scholar 

  40. Burla MC, Caliandro R, Camalli M, Carrozzini B, Cascarano GL, De Caro L, Giacovazzo C, Polidori G, Spagna R (2005) SIR2004: an improved tool for crystal structure determination and refinement. J Appl Crystallogr 38:381–388. https://doi.org/10.1107/s002188980403225x

    Article  CAS  Google Scholar 

  41. Sheldrick G (2015) Crystal structure refinement with SHELXL. Acta Crystallogr Sect C Struct Chem 71:3–8. https://doi.org/10.1107/s2053229614024218

    Article  Google Scholar 

  42. Sheldrick GM (1996) SADABS, programs for scaling and correction of area detection data. University of Göttingen, Göttingen

    Google Scholar 

  43. Neese F (2012) The ORCA program system. Wiley Interdiscipl Rev Comput Mol Sci 2:73–78. https://doi.org/10.1002/wcms.81

    Article  CAS  Google Scholar 

  44. Neese F (2018) Software update: the ORCA program system, version 4.0. Wiley Interdiscipl Rev Comput Mol Sci 8:e1327. https://doi.org/10.1002/wcms.1327

    Article  Google Scholar 

  45. Mardirossian N, Head-Gordon M (2016) ωB97M-V: a combinatorially optimized, range-separated hybrid, meta-GGA density functional with VV10 nonlocal correlation. J Chem Phys 144:214110. https://doi.org/10.1063/1.4952647

    Article  CAS  PubMed  Google Scholar 

  46. Mardirossian N, Ruiz Pestana L, Womack JC, Skylaris C-K, Head-Gordon T, Head-Gordon M (2017) Use of the rVV10 nonlocal correlation functional in the B97M-V density functional: defining B97M-rV and related functionals. J Phys Chem Lett 8:35–40. https://doi.org/10.1021/acs.jpclett.6b02527

    Article  CAS  PubMed  Google Scholar 

  47. Weigend F, Ahlrichs R (2005) Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: design and assessment of accuracy. Phys Chem Chem Phys 7:3297–3305. https://doi.org/10.1039/b508541a

    Article  CAS  PubMed  Google Scholar 

  48. Weigend F (2006) Accurate Coulomb-fitting basis sets for H to Rn. Phys Chem Chem Phys 8:1057–1065. https://doi.org/10.1039/b515623h

    Article  CAS  PubMed  Google Scholar 

  49. Glendening ED, Badenhoop JK, Reed AE, Carpenter JE, Bohmann JA, Morales CM, Karafiloglou P, Landis CR, Weinhold F (2018) NBO 70. Theoretical Chemistry Institute, University of Wisconsin, Madison

    Google Scholar 

  50. Syed Mohamed K, Padma DK (1985) Spectral studies on pyridinium hexafluorophosphate. Spectrochim Acta Part A 41:725–728. https://doi.org/10.1016/0584-8539(85)80181-1

    Article  Google Scholar 

  51. Mayfield HG, Bull WE (1971) Co-ordinating tendencies of the hexafluorophosphate ion. J Chem Soc A. https://doi.org/10.1039/j19710002279

  52. Only data for complexes 3a–e are displayed in Table 2, see Ref. 26 for complexes 4a–e

  53. Bauzá A, Quiñonero D, Deyà PM, Frontera A (2013) Halogen bonding versus chalcogen and pnicogen bonding: a combined Cambridge structural database and theoretical study. CrystEngComm 15:3137–3144. https://doi.org/10.1039/c2ce26741a

    Article  CAS  Google Scholar 

  54. Pascoe DJ, Ling KB, Cockroft SL (2017) The origin of chalcogen-bonding interactions. J Am Chem Soc 139:15160–15167. https://doi.org/10.1021/jacs.7b08511

    Article  CAS  PubMed  Google Scholar 

  55. Scilabra P, Terraneo G, Resnati G (2019) The chalcogen bond in crystalline solids: a world parallel to halogen bond. Acc Chem Res 52:1313–1324. https://doi.org/10.1021/acs.accounts.9b00037

    Article  CAS  PubMed  Google Scholar 

  56. Vogel L, Wonner P, Huber SM (2019) Chalcogen bonding: an overview. Angew Chem Int Ed 58:1880–1891. https://doi.org/10.1002/anie.201809432

    Article  CAS  Google Scholar 

  57. Beno BR, Yeung K-S, Bartberger MD, Pennington LD, Meanwell NA (2015) A survey of the role of noncovalent sulfur interactions in drug design. J Med Chem 58:4383–4438. https://doi.org/10.1021/jm501853m

    Article  CAS  PubMed  Google Scholar 

  58. Mahmudov KT, Aliyeva VA, Guedes da Silva MFC, Pombeiro AJL (2021) The chalcogen bond in solution: synthesis, catalysis and molecular recognition. In: Huber SM (ed) Halogen bonding in solution. Wiley-VCH, Weinheim, pp 363–382. https://doi.org/10.1002/9783527825738.ch11

    Chapter  Google Scholar 

  59. Vydrov OA, Van Voorhis T (2010) Nonlocal van der Waals density functional: the simpler the better. J Chem Phys 133:244103. https://doi.org/10.1063/1.3521275

    Article  CAS  PubMed  Google Scholar 

  60. Iron MA, Janes T (2019) Evaluating transition metal barrier heights with the latest density functional theory exchange-correlation functionals: the MOBH35 benchmark database. J Phys Chem A 123:3761–3781. https://doi.org/10.1021/acs.jpca.9b01546

    Article  CAS  PubMed  Google Scholar 

  61. Iron MA, Janes T (2019) Correction to “Evaluating transition metal barrier heights with the latest density functional theory exchange-correlation functionals: the MOBH35 benchmark database.” J Phys Chem A 123:6379–6380. https://doi.org/10.1021/acs.jpca.9b06135

    Article  CAS  PubMed  Google Scholar 

  62. Berger G, Leclercqz H, Derenne A, Gelbcke M, Goormaghtigh E, Nève J, Mathieu V, Dufrasne F (2014) Synthesis and in vitro characterization of platinum(II) anticancer coordinates using FTIR spectroscopy and NCI COMPARE: a fast method for new compound discovery. Bioorg Med Chem 22:3527–3536. https://doi.org/10.1016/j.bmc.2014.04.017

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Johann Far for the ESI-MS analyses, Mr Stéphane Luts and Prof. Gauthier Eppe for the FT-IR analyses, and RIAIDT-USC for the use of its analytical facilities.

Funding

Financial support from the Fonds de la Recherche Scientifique—FNRS under CDR Grants J.0155.18 and J.0013.23 is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Laboratory of Catalysis, MolSys Research Unit, Institut de Chimie Organique (B6a), Université de Liège, Allée du Six Août 13, 4000, Liège, Belgium

    Mohammed Zain Aldin & Lionel Delaude

  2. Unidade de Difracción de Raios X, RIAIDT, Universidade de Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Spain

    Guillermo Zaragoza

  3. Microbiology, Bioorganic and Macromolecular Chemistry, Faculté de Pharmacie, Université Libre de Bruxelles, 1050, Brussels, Belgium

    Eva Choquenet, Guillaume Blampain & Gilles Berger

Authors
  1. Mohammed Zain Aldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guillermo Zaragoza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva Choquenet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guillaume Blampain
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gilles Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lionel Delaude
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lionel Delaude.

Ethics declarations

Conflict of interest

All authors declares that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 3249 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zain Aldin, M., Zaragoza, G., Choquenet, E. et al. Synthesis, characterization, and biological activity of cationic ruthenium–arene complexes with sulfur ligands. J Biol Inorg Chem (2024). https://doi.org/10.1007/s00775-024-02052-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00775-024-02052-2

Keywords

Search

Navigation