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. 2009 Feb 2;48(3):1122-31.
doi: 10.1021/ic802220w.

Synthesis, characterization, and in vitro antimalarial and antitumor activity of new ruthenium(II) complexes of chloroquine

Chandima S K Rajapakse  1 , Alberto Martínez, Becky Naoulou, Andrzej A Jarzecki, Liliana Suárez, Christiane Deregnaucourt, Véronique Sinou, Joseph Schrével, Elgilda Musi, Grazia Ambrosini, Gary K Schwartz, Roberto A Sánchez-Delgado
Affiliations

Synthesis, characterization, and in vitro antimalarial and antitumor activity of new ruthenium(II) complexes of chloroquine

Chandima S K Rajapakse et al. Inorg Chem. .

Abstract

The new Ru(II) chloroquine complexes [Ru(eta(6)-arene)(CQ)Cl2] (CQ = chloroquine; arene = p-cymene 1, benzene 2), [Ru(eta(6)-p-cymene)(CQ)(H2O)2][BF4]2 (3), [Ru(eta(6)-p-cymene)(CQ)(en)][PF6]2 (en = ethylenediamine) (4), and [Ru(eta(6)-p-cymene)(eta(6)-CQDP)][BF4]2 (5, CQDP = chloroquine diphosphate) have been synthesized and characterized by use of a combination of NMR and FTIR spectroscopy with DFT calculations. Each complex is formed as a single coordination isomer: In 1-4, chloroquine binds to ruthenium in the eta(1)-N mode through the quinoline nitrogen atom, whereas in 5 an unprecedented eta(6) bonding through the carbocyclic ring is observed. 1, 2, 3, and 5 are active against CQ-resistant (Dd2, K1, and W2) and CQ-sensitive (FcB1, PFB, F32, and 3D7) malaria parasites (Plasmodium falciparum); importantly, the potency of these complexes against resistant parasites is consistently higher than that of the standard drug chloroquine diphosphate. 1 and 5 also inhibit the growth of colon cancer cells, independently of the p53 status and of liposarcoma tumor cell lines with the latter showing increased sensitivity, especially to 1 (IC50 8 microM); this is significant because this type of tumor does not respond to currently employed chemotherapies.

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Figures

Fig. 1
Fig. 1
Optimized structures for complexes 1’ and 5.
Fig. 2
Fig. 2
IR spectra for complex 1. Spectra A and B are DFT simulated for the two isomers of complex 1. Bottom spectrum is an experimental measurement.
Scheme 1
Scheme 1
Synthesis of new Ru-chloroquine complexes a(i) [Ru(η6-arene)Cl2]2 (arene = p-cymene, Me2CO, 25 °C; benzene, acetonitrile, 25 °C); (ii) [(Ru η6-p-cymene)Cl2]2/AgBF4 (1:4), Me2CO, 55 °C, 3 isolated as the BF4 salt; (iii) AgBF4 (1:1), Me2CO, 55 °C, 3 isolated as the BF4 salt; (iv) [Ru(η6-p-cymene)Cl(en)][PF6]/AgPF6 (1:1), MeOH, 25 °C, 4 isolated as the PF6 salt; (v) CQ used as the diphosphate salt CQDP, [Ru(η6-p-cymene)Cl2]2/AgBF4 (1:4), H2O, 55 °C, 5 isolated as the BF4 salt.
Chart 1
Chart 1
Examples of metal derivatives of chloroquine with antimalarial properties.
Chart 2
Chart 2
Possible coordination modes of CQ and CQDP in Ru complexes.
Chart 3
Chart 3
Structural Assignments for Complexes 1–5.
See this image and copyright information in PMC

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