Antitumor Carbohydrate-Substituted Arene and Tetrazene Ruthenium(Ii) Complexes

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Antitumor Carbohydrate-Substituted Arene and Tetrazene Ruthenium(Ii) Complexes

Jiri Pinkas 2 , Roman Hrstka 3 , Hana Skoupilova 3 , Jindrich Karban 1

1 Institute of Chemical Process Fundamentals of the CAS, v. v. i., Rozvojova 135, 165 02 Praha, Czech Republic, 2 J. Heyrovsky Institute of Physical Chemistry of the CAS, v. v. i., Dolejskova 3, 182 23 Praha, Czech Republic, 3 RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic

Successful introduction of cytotoxic cisplatin and related platinum complexes in clinical practice initiated research into antitumor properties of organometallic and coordination complexes. Ruthenium complexes belong to the most promising antitumor drug candidates. For example, half-sandwich Ru(II) arene complexes such as RAPTA-T ([Ru(η⁶-C₆H₅Me)Cl₂(pta)]) and RAPTA-C ([Ru(η⁶-p-cymene)Cl₂(pta)] (where pta = 1,3,5-triaza-7-phosphaadamantane) have been developed and thoroughly investigated. RAPTA-T exhibits remarkable selectivity against metastatic tumors in vivo [1], whereas RAPTA-C also shows promising angiostatic activity [2]. In contrast to widely studied half-sandwich ruthenium η⁶-arene complexes, stabile 18-electron cationic full-sandwich ruthenium complexes of the general formula ([Ru(η⁶-arene)(η⁵-Cp*)]+A- (where Cp* is pentamethylcyclopentadienyl and A- represents an uncoordinated anion) received less attention. An interesting cytotoxic activity has been reported for some of them [3-5], but antimetastatic activity of these cationic complexes has not been investigated.

We have prepared a series of Ru(II) complexes of the general formula [Ru(η⁶-arene)(η⁵-Cp*)]+ Cl−, where the arene ligand is the phenyl moiety of benzyl hexopyranosides or benzyl ether-protected hexopyranoses. These complexes had negligible cytotoxicity, but some of them, in particular complex (1), showed anti-migratory and anti-invasive effects in vitro comparable to those of the reference compounds RAPTA-C and RAPTA-T.

Furthermore, we have also prepared Ru(II) complexes with carbohydrate-substituted chelate tetrazene ligand. These tetrazene complexes had variable cytotoxicity. The most active was complex (2), which exhibited cytotoxicity in low micromolar range.

Examples of antitumor carbohydrate-substituted Ru(II) complexes

Financial Support of the Czech Science Foundation is gratefully acknowledged (Project GA 17-05838S)

Ang, W. H.; Casini, A.; Sava, G.; Dyson, P. J. Organometallic ruthenium-based antitumor compounds with novel modes of action. J. Organomet. Chem. 2011, 696, 989-998.

Berndsen, R. H.; Weiss, A.; Abdul, U. K.; Wong, T. J.; Meraldi, P.; Griffioen, A. W.; Dyson, P. J.; Nowak-Sliwinska, P. Combination of ruthenium(II)-arene complex [Ru(η⁶-p-cymene)Cl₂(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity. Scientific Reports 2017, 7, 43005.

Loughrey, B. T.; Healy, P. C.; Parsons, P. G.; Williams, M. L. Selective Cytotoxic Ru(II) Arene Cp* Complex Salts [R-PhRuCp*]+X− for X = BF₄−, PF₆−, and BPh₄−. Inorg. Chem. 2008, 47, 8589- 8591.

Loughrey, B. T.; Cunning, B. V.; Healy, P. C.; Brown, C. L.; Parsons, P. G.; Williams, M. L. Selective, Cytotoxic Organoruthenium(II) Full-Sandwich Complexes: A Structural, Computational and In Vitro Biological Study. Chemistry – An Asian Journal 2012, 7, 112-121.

Loughrey, B. T.; Williams, M. L.; Parsons, P. G.; Healy, P. C. Nucleophilic substitution reactions of [(η⁵-Cp*)Ru(η⁶-C₆H₅CO₂H)]+: Synthesis, characterization and cytotoxicity of organoruthenium ester and amide complexes. J. Organomet. Chem. 2016, 819, 1-10.

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