Toward a novel metal-based chemotherapy against tropical diseases. 1. Enhancement of the efficacy of clotrimazole against Trypanosoma cruzi by complexation to ruthenium in RuCl2(clotrimazole)2

The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

“…We have previously discussed the concept of enhancing the activity of organic compounds of known therapeutic value by coordination to a metalcontaining fragment through a metal-drug synergy [21,22]. We demonstrated the merit of this approach against Trypanosoma cruzi, the causative agent of Chagas disease, using metal complexes of clotrimazole and ketoconazole [23][24][25][26]; some of those complexes were also found to be active as antitumor agents [27]. We also modified CQ through coordination to metalcontaining fragments, notably ruthenium [28], rhodium [28], and gold [29,30], and found enhanced antimalarial activity in several instances.…”

Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

“…Since genetic alterations involving p53 mutation frequently correlate with decreased response to cancer chemotherapy, 9,10 we investigated whether Ru(II) complexes with CTZ or KTZ [11][12][13] are more effective than the parent compounds at promoting cell death in tumors with such genetic changes. The reason for this study with Ru(II)-azole complexes is to expand the range of potentially useful antitumor Ru agents since an Ru(III) complex like NAMI-A, 14 -16 which may require reduction of its Ru(III) moiety to act, has shown promising anticancer activity in initial clinical trials.…”

“…The mitochondrial damage induced by NAMI-A 16 is compatible with the effect of 20 -50 M CTZ, which induces glycolysis-related hexokinase detachment from mitochondria and loss of viability in B16 melanoma. 8 Since apoptosis induced by 50 M KTZ is decreased in colorectal and hepatocellular carcinoma cell lines with a defective p53-dependent pathway, 7 which also hampers the efficacy of cisplatin, 9,10 we investigated whether KTZ-Ru(II) complexes [11][12][13] are more active than KTZ or Ru(II) alone against tumor cells harboring p53 mutation. 19,20 We also investigated some of the mechaAbbreviations: CTZ, clotrimazole, 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole; EGF-R, epidermal growth factor receptor; IC 50 , concentration that inhibits 50%; KTZ, ketoconazole, cis 4 , dichlorotetrakis(acetonitrile) Ru(II); wt, wild type; [X( 6 -arene)(en)Ru(II)], X ϭ Cl, MeCN, arene ϭ benzene, p-cymene, en ϭ 1,2-ethylenediamine; cisplatin, cis-diamminedichloroplatinum(II).…”

The role of nanogold in human tropical diseases: research, detection and therapy

“…A series of seven papers regarding metal-based chemotherapy against tropical diseases was published by Sánchez-Delgado and co-workers [33][34][35][36][37][38][39], from 1993 to 2004. Navarro, who wrote a very interesting review in 2009 about gold complexes as potential anti-parasitic agents [40], published since 1997, together with different co-workers, also some papers in this series [35,36,38,39].…”

“…Concerning antimalarial gold compounds, and in context of the already mentioned series of seven papers related to metal-based chemotherapy against tropical diseases [33][34][35][36][37][38][39], Navarro et al described the reaction of AuPPh 3 Cl with chloroquine (CQ) and KPF 6 leading to the new complex [Au(PPh 3 )(CQ)]PF 6 . This compound was found to be considerably more active than CQ diphosphate and other previously reported metal-CQ complexes (Ru or Rh [34]) against two chloroquine-resistant strains of P. falciparum in vitro [35].…”