Ingo Ott

ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTOrganometallic Anticancer CompoundsGilles Gasser*†§, Ingo Ott*‡, and Nils Metzler-Nolte*§View Author Information† Institute of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland‡ Institute of Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany§ Chair of Inorganic Chemistry I, Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany*To whom correspondence should be addressed. For G.G.: phone, +41(0)44 635-4611; fax, +41(0)44 635-6803; e-mail, [email protected]; Web page, www.gassergroup.com. For I.O.: phone, +49 (0)531-391 2743; fax, +49 (0)531-391 8456; e-mail, [email protected]; Web page, www.pharmchem.tu-bs.de/forschung/ott/. For N.M.-N.: phone, +49 (0)234-32 28152; fax, +49 (0)234-32 14378; e-mail, [email protected]; Web page, www.chemie.rub.de/ac1.Cite this: J. Med. Chem. 2011, 54, 1, 3–25Publication Date (Web):November 15, 2010Publication History Received8 January 2010Published online15 November 2010Published inissue 13 January 2011https://doi.org/10.1021/jm100020wCopyright © 2010 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceArticle Views34024Altmetric-Citations1313LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (3 MB) Get e-AlertscloseSUBJECTS:Genetics,Ligands,Metals,Reaction products,Sandwich compounds Get e-Alerts

The development of metal complexes with platinum central atoms such as cisplatin or carboplatin had an enormous impact on current cancer chemotherapy. However, the spectrum of cancers that can be treated with platinum agents is narrow and treatment efficacy suffers from side effects and resistance phenomena. These unresolved problems in platinum-based anti-cancer therapy have stimulated increased research efforts in the search for novel non platinum-containing metal species as cytostatic agents. Preclinical and clinical investigations showed that the development of new metal agents with modes of action different from cisplatin is possible. Thus, complexes with iron, cobalt, or gold central atoms have shown promising results in preclinical studies and compounds with titanium, ruthenium, or gallium central atoms have already been evaluated in phase I and phase II trials. This review covers some relevant examples of preclinical and clinical research on novel non platinum metal complexes.

Metal complexes with N-heterocyclic carbene (NHC) ligands are widely used in chemistry due to their catalytic properties and applied for olefin metathesis among other reactions. The enhanced application of this type of organometallics has over the last few years also triggered a steadily increasing number of studies in the fields of medicinal chemistry, which take advantage of the fascinating chemical properties of these complexes. In fact it has been demonstrated that metal NHC complexes can be used to develop highly efficient metal based drugs with possible applications in the treatment of cancer or infectious diseases. Complexes of silver and gold have been biologically evaluated most frequently but also platinum or other transition metals have demonstrated promising biological properties.

Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.