Dalton Transactions View Article Online PERSPECTIVE View Journal Anticancer activity of complexes of the third row transition metals, rhenium, osmium, and iridium Cite this: DOI: 10.1039/c8dt01858h Chilaluck C. Konkankit,† Sierra C. Marker,† Kevin M. Knopf and Justin J. Wilson * The clinical success of the platinum-based chemotherapeutic agents has prompted the investigation of coordination and organometallic complexes of alternative metal centers for use as anticancer agents. Among these alternatives, the third row transition metal neighbors of platinum on the periodic table have only recently been explored for their potential to yield anticancer-active complexes. In this Perspective, we summarize developments within the last six years on the application of rhenium, osmium, and iridium complexes as anticancer drug candidates. This review focuses on studies that discuss the potential Received 8th May 2018, mechanisms of action of these complexes. As reflected in this Perspective, complexes of these metal ions Accepted 6th June 2018 induce cancer cell death via a diverse range of mechanisms. Notably, small structural changes can signifi- DOI: 10.1039/c8dt01858h cantly alter the mode of cell death, hindering efforts to elucidate structure–activity relationships. This rsc.li/dalton property may both benefit and hinder the clinical development of these compounds. – 1. Introduction development of targeted therapies.2 4 These targeted approaches rely on the overexpression of specific receptors on Despite significant advances over the last fifty years, cancer cancer cells. In principle, targeted therapy provides a means to remains one of the leading causes of death worldwide.1 In con- treat cancer without the off-target side effects associated with junction with surgical resection and radiotherapy, chemo- cytotoxic chemotherapeutic agents, but it is limited to cancers therapy, the application of cytotoxic chemical compounds, is that exhibit specific targetable genotypes. For patients with still the predominant strategy for cancer treatment. The toxic cancers lacking these desired genotypes, chemotherapy side effects associated with chemotherapeutic treatment regi- remains the primary therapeutic option. As such, there is a Published on 15 June 2018. Downloaded by Cornell University Library 7/19/2018 12:03:27 AM. mens, however, have directed research efforts towards the need to develop more effective chemotherapeutic agents with superior toxicity profiles. Among the most effective and well-studied class of chemo- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA. E-mail: [email protected] therapeutic agents are the platinum-based drugs, which †These authors contributed equally to this work. comprise the FDA-approved compounds, cisplatin, carbopla- Chilaluck Charlene Konkankit Sierra Marker grew up in grew up in southern California, central New York, USA. She USA. She obtained her B.S. received her B.S. degree in degree in Chemistry from the Biochemistry from Binghamton University of California, Irvine University (2015) and her M.S. (2015) and her M.S. degree in degree in Inorganic Chemistry Inorganic Chemistry from from Cornell University (2017). Cornell University (2017). She is She is currently pursuing her Ph. currently a Ph.D. student under D. at Cornell University under the supervision of Prof. Justin the supervision of Prof. Justin J. Wilson. Her project focuses on J. Wilson. Her project focuses on the design of novel rhenium tri- the utilization of rhenium tricar- Chilaluck C. Konkankit carbonyl complexes as theranos- Sierra C. Marker bonyl complexes as photoacti- tic anticancer agents. vated anticancer agents. This journal is © The Royal Society of Chemistry 2018 Dalton Trans. View Article Online Perspective Dalton Transactions tin, and oxaliplatin.5 These drugs, whose mechanisms of platinum. More closely aligned chemistry can be found for action rely on the formation of covalent Pt–DNA adducts,6 elements that directly neighbor platinum in the third row of suffer from many of the limitations of chemotherapy. Namely, the transition metals, namely rhenium, osmium, and – they induce toxic side effects,7 such as nephrotoxicity, ototoxi- iridium.17 19 A potential advantage of complexes of these city, and peripheral neuropathy, which limit the doses that can metal ions is their structural diversity compared to the typical 8 be safely administered to patients. In addition, cancer cells square planar Pt(II) complexes. The unique molecular architec- readily develop resistance to these drugs, rendering them tures of these complexes may enable novel modes of inter- useless for most relapsed forms of this disease.9 In spite of action with biomolecular targets.20 As such, there has been an these limitations, the platinum drugs are still the first line increasing number of investigations exploiting the attractive treatment for many cancer types as evidenced by their use in chemical properties of these elements for the development of approximately 50% of all chemotherapeutic treatment regi- anticancer agents. mens.10 Although continued efforts to improve upon platinum In this Perspective, we summarize recent investigations of anticancer agents have been made,11,12 there have been no anticancer agents comprising the elements, rhenium, new drugs of this class brought to the market in the United osmium, and iridium. The scope of this article is restricted States since the FDA approval of oxaliplatin in 2002.13 to developments within the last six years, describing earlier Given the clinical success of the platinum-based com- studies only when necessary to give appropriate context for pounds, extensive research efforts have been directed towards recent investigations. Additionally, an emphasis is placed on investigating the anticancer activity of complexes of alternative studies that investigated the mechanisms of action and metal ions. The aim of these studies is to capitalize on the in vivo properties of these complexes. Although a number of – novel therapeutic potential of inorganic complexes, while cir- recent studies have demonstrated the use of rhenium,21 26 cumventing the limitations of the platinum drugs.14 The osmium,27,28 and iridium29,30 complexes as photodynamic or majority of these efforts have focused on complexes of ruthe- photoactivated therapeutic agents, these light-activated com- nium, gold, and titanium.15 Although several of these com- pounds are beyond the scope of this Perspective. Collectively, pounds have shown extremely promising activity that has war- the results summarized in this Perspective highlight the ranted clinical trials, their chemistry is significantly different valuable anticancer activity of these complexes and demon- from that of platinum.16 Specifically, their ligand substitution strate their growing potential as novel chemotherapeutic kinetics are several orders of magnitude larger than those of agents. Kevin Knopf grew up in Justin Wilson originates from Connecticut, USA. He obtained Orange County, California, USA. his B.S. degree in Chemistry He obtained his B.S. degree in from Central Connecticut State Chemistry from the University of Published on 15 June 2018. Downloaded by Cornell University Library 7/19/2018 12:03:27 AM. University (2015) and his M.S. California, Berkeley (2008), degree in Inorganic Chemistry which was awarded with Highest from Cornell University (2017). Honors and the Departmental Citation. Justin carried out his Ph.D. studies under the mentor- ship of Prof. Stephen J. Lippard at the Massachusetts Institute of Technology on the topic of plati- Kevin M. Knopf Justin J. Wilson num-based anticancer agents. He received the Davison Prize for his thesis, an annual prize awarded for the best inorganic thesis at MIT. Following completion of his graduate studies in 2013, Justin assumed a position as a Seaborg Institute Postdoctoral Fellow at Los Alamos National Laboratory (LANL), where he worked under the guidance of Dr. Eva Birnbaum in the Isotope Production Program. His work at LANL focused on the radiochem- istry of therapeutic alpha-emitting radionuclides. Since assuming his independent position as an Assistant Professor of Chemistry and Chemical Biology at Cornell University in 2015, Justin’s research efforts have been focused broadly on novel implemen- tations of metals in medicine. Dalton Trans. This journal is © The Royal Society of Chemistry 2018 View Article Online Dalton Transactions Perspective 2. Rhenium complexes cytotoxic than the corresponding rhenium complex, suggesting that the mode of DNA binding might play an important role in Complexes of rhenium have long been neglected as potential the anticancer activity of these compounds. Similarly, the lipo- anticancer agents. Only recently have a number of investi- philic rhenium complexes, 2a and 2b, which both bear axial gations arisen that demonstrate the potent anticancer activity pyridine ligands containing a long alkyl chain, interact with of these complexes.31 Rhenium attains a wide range of oxi- the minor groove of DNA.41 Molecular docking studies confirm dation states and, as such, supports a diverse set of different that the alkyl chain plays a key role in DNA binding because it ligand types and coordination geometries. Arguably, the most allows for the complex to attain the proper orientation for common structural motif applied in biological systems is the fitting within the minor groove. The DNA-binding abilities of 32 stable Re(I) tricarbonyl core. By leveraging their rich spectro-