View source for Ruthenium anti-cancer drugs

'''Ruthenium anti-cancer drugs''' are [[coordination complex]]es of [[ruthenium]] complexes that have anticancer properties.  They promise to provide alternatives to [[platinum]]-based drugs for anticancer therapy.<ref name="ana">{{cite journal |doi=10.1007/s00280-010-1293-1 |title=Ruthenium-based chemotherapeutics: Are they ready for prime time? |year=2010 |last1=Antonarakis |first1=Emmanuel S. |last2=Emadi |first2=Ashkan |journal=Cancer Chemotherapy and Pharmacology |volume=66 |pages=1–9 |pmid=20213076 |issue=1 |pmc=4020437}}</ref><ref name="main">{{cite journal |doi=10.1016/j.jinorgbio.2011.09.030 |title=Approaching tumour therapy beyond platinum drugs |year=2012 |last1=Bergamo |first1=A. |last2=Gaiddon |first2=C. |last3=Schellens |first3=J.H.M. |last4=Beijnen |first4=J.H. |last5=Sava |first5=G. |journal=Journal of Inorganic Biochemistry |volume=106 |pages=90–9 |pmid=22112845 |issue=1}}</ref>  No ruthenium anti-cancer drug has been commercialized.
Since 1979, when  Cisplatin entered clinical trials, there has been continuing interest in alternative metal-based drugs.<ref>{{cite journal |doi=10.1016/S0162-0134(00)80045-8 |title=Reduction and Subsequent Binding of Ruthenium Ions Catalyzed by Subcellular Components |year=1980 |last1=Clarke |first1=M.J. |last2=Bitler |first2=S. |last3=Rennert |first3=D. |last4=Buchbinder |first4=M. |last5=Kelman |first5=A.D. |journal=Journal of Inorganic Biochemistry |volume=12 |pages=79–87 |pmid=7373292 |issue=1}}</ref>  The leading ruthenium-based candidates are [[BOLD-100]] and TLD-1433. Other ruthenium based therapeutics that have been tested clinically include [[NAMI-A]] and [[KP1019]]. The first ruthenium-based drug to enter clinical trials was NAMI-A. More ruthenium drugs are still under development. Ruthenium complexes as anticancer drugs were originally designed to mimic platinum drugs for targeting DNA,<ref name="one" /> but emerging ruthenium compounds have shown a variety of mechanisms of actions, which include [[reactive oxygen species|ROS]] generation, and as [[Endoplasmic reticulum]] stress agents.<ref>{{Cite journal|last1=Mjos|first1=Katja Dralle|last2=Orvig|first2=Chris|date=2014-04-23|title=Metallodrugs in Medicinal Inorganic Chemistry|journal=Chemical Reviews|language=en|volume=114|issue=8|pages=4540–4563|doi=10.1021/cr400460s|pmid=24456146|issn=0009-2665|doi-access=free}}</ref>
==Properties of ruthenium complexes==
[[Ruthenium]] has numerous properties that qualify it as an [[chemotherapy|antineoplastic drug]] contender.<ref name="one">{{cite journal |doi=10.1039/C0DT01816C |title=Ruthenium anticancer compounds: Myths and realities of the emerging metal-based drugs |year=2011 |last1=Bergamo |first1=Alberta |last2=Sava |first2=Gianni |journal=Dalton Transactions |volume=40 |issue=31 |pages=7817–23 |pmid=21629963}}</ref><ref name="seven">{{cite journal |doi=10.2174/138955709790361566 |title=New Platinum and Ruthenium Complexes - the Latest Class of Potential Chemotherapeutic Drugs - a Review of Recent Developments in the Field |year=2009 |last1=Amin |first1=Amr |last2=Buratovich |first2=Michael |journal=Mini-Reviews in Medicinal Chemistry |volume=9 |issue=13 |pages=1489–503 |pmid=20205631}}</ref>
===Oxidation states and geometry===
Ruthenium complexes typically adopt [[oxidation states]] II and III<ref name="eleven">{{cite magazine |last=Page |first=Simon |date=1 January 2012 |title=Ruthenium compounds as anticancer agents |magazine=[[Education in Chemistry]] |url=https://eic.rsc.org/feature/ruthenium-compounds-as-anticancer-agents/2020225.article |publisher=[[Royal Society of Chemistry]] |volume=49 |issue=1 |pages=26–29 }}</ref>  The geometry assumed by most ruthenium complexes is [[Octahedral molecular geometry|octahedral]], which differs from the [[square planar molecular geometry]] typical for platinum(II). The presence of six ligands allows for tuning of the complexes' [[electronic effect|electronic]] and [[steric effects|steric]] properties.<ref name="ana" /><ref name="four">{{cite journal |doi=10.1016/j.jorganchem.2010.11.009 |title=Organometallic ruthenium-based antitumor compounds with novel modes of action |year=2011 |last1=Ang |first1=Wee Han |last2=Casini |first2=Angela |authorlink2=Angela Casini |last3=Sava |first3=Gianni |last4=Dyson |first4=Paul J. |journal=Journal of Organometallic Chemistry |volume=696 |issue=5 |pages=989–98}}</ref><ref>{{cite journal | vauthors = Gopal YN, Jayaraju D, Kondapi AK | title = Inhibition of topoisomerase II catalytic activity by two ruthenium compounds: a ligand-dependent mode of action | journal = Biochemistry | volume = 38 | issue = 14 | pages = 4382–8 | date = April 1999 | pmid = 10194357 | doi = 10.1021/bi981990s }}</ref>  Its partially filled 4d sub-shell allows it to form complexes that are useful for a wide variety of applications including catalysis, electronics, photochemistry, biosensors and anticancer drugs.<ref name=clinical_trial>{{cite journal | vauthors = Kostova I | title = Ruthenium complexes as anticancer agents | journal = Current Medicinal Chemistry | volume = 13 | issue = 9 | pages = 1085–107 | year = 2006 | pmid = 16611086 | doi = 10.2174/092986706776360941 }}</ref><ref>{{cite journal | vauthors = Antonarakis ES, Emadi A | title = Ruthenium-based chemotherapeutics: are they ready for prime time? | journal = Cancer Chemotherapy and Pharmacology | volume = 66 | issue = 1 | pages = 1–9 | date = May 2010 | pmid = 20213076 | pmc = 4020437 | doi = 10.1007/s00280-010-1293-1 }}</ref>
===Ligand exchange rates===
The rate of [[ligand exchange]] for ruthenium complexes is relatively slow in comparison with other transition metal complexes. The range of these exchange rates is around 10<sup>−2</sup> to 10<sup>−4</sup>&nbsp;s<sup>−1</sup> which is on the scale of an average cell’s lifetime, giving the drug high kinetic stability and minimizing side reactions.<ref name="ana"/> This allows the Ru complex to remain intact as it approaches the target as well as remain viable throughout its interaction with the cells. It is also possible through ligand variation to precisely tune the exchange kinetics, allowing a large degree of control over the complex’s stability.<ref name="six">{{cite book |doi=10.1016/S0898-8838(09)00201-3 |pmid=21258628 |pmc=3024542 |title=Controlling platinum, ruthenium, and osmium reactivity for anticancer drug design |series=Advances in Inorganic Chemistry |year=2009 |last1=Bruijnincx |first1=Pieter C.A. |last2=Sadler |first2=Peter J. |isbn=9780123750334 |volume=61 |pages=1–62}}</ref>
===Activation===
The theory of "activation by reduction" is based on the understanding that Ru(II) complexes are generally more reactive than Ru(III) complexes. As cancer cells are generally growing and multiplying much more rapidly than normal healthy cells, this creates an environment that is less oxygen-rich due to the raised [[metabolic rate]]. When this is paired with the tendency of cancerous cells to contain higher levels of [[glutathione]] and a lower [[pH]], a chemically reducing environment is created.<ref name="ana"/> This theoretically allows for ruthenium complexes to be administered as much less active, non-toxic Ru(III) compounds (as a [[prodrug]]), which can be activated solely at the site of the cancerous cells.<ref name="ana"/> The reduction is thought to occur by mitochondrial proteins or microsomal single electron transfer proteins, though it may also occur by [[membrane protein|trans-membrane electron transport]] systems which reside outside the cell – implying that entry to the cancerous cells may not be required for the drug to be effective.<ref name="eleven"/> In theory it is also possible for the ruthenium compounds to be oxidized back to their inactive form if it leaves the cancerous environment. This phenomenon remains a theory, and has been primarily demonstrated ''[[in vitro]]''.<ref name="one"/>
Although this theory is attractive, convenient, and grounded in fundamental ruthenium chemistry, this theory falls apart when investigated under ''[[in vivo]]''. A direct contradiction of this theory was proven using [[XANES]] and [[BOLD-100]]. This study examined several tissues (tumor included) of SW480-bearing mice for 24 hours after administration of [[BOLD-100]]. This study showed that the Ru(III) oxidation state persists, and since [[BOLD-100]] has significant biological effects within that 24-hour time point, this directly contradicts the "activation by reduction" mechanism.<ref>{{cite journal |last1=Blazevic |first1=Amir |last2=Hummer |first2=Alfred A. |last3=Heffeter |first3=Petra |last4=Berger |first4=Walter |last5=Filipits |first5=Martin |last6=Cibin |first6=Giannantonio |last7=Keppler |first7=Bernhard K. |last8=Rompel |first8=Annette |title=Electronic State of Sodium trans-[Tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) in Tumor, Liver and Kidney Tissue of a SW480-bearing Mouse |journal=Scientific Reports |date=23 January 2017 |volume=7 |issue=1 |pages=40966 |doi=10.1038/srep40966|pmid=28112202 |pmc=5256101 |bibcode=2017NatSR...740966B }}</ref>
===Biological transportation===
[[File:PDB 1AO6-HSA.png|thumb|3D rendering of [[human serum albumin]] (HSA)]]
The ruthenium complex  [[BOLD-100]] binds to [[serum albumin]] as established by [[X-ray crystallography]]. This adduct is proposed to facilitate uptake.<ref>{{cite journal |last1=Bijelic |first1=Aleksandar |last2=Theiner |first2=Sarah |last3=Keppler |first3=Bernhard K. |last4=Rompel |first4=Annette |title=X-ray Structure Analysis of Indazolium trans- [Tetrachlorobis(1 H -indazole)ruthenate(III)] (KP1019) Bound to Human Serum Albumin Reveals Two Ruthenium Binding Sites and Provides Insights into the Drug Binding Mechanism |journal=Journal of Medicinal Chemistry |date=23 June 2016 |volume=59 |issue=12 |pages=5894–5903 |doi=10.1021/acs.jmedchem.6b00600|pmid=27196130 |pmc=4921950 }}</ref> The levels of [[serum albumin]] in these cancerous cells are greatly increased, which may contribute to the lower toxicity associated to the ruthenium drugs in comparison to platinum.<ref name="six"/>
==Prospective ruthenium anti-cancer drugs==
===BOLD-100===
[[BOLD-100]], or sodium trans-[tetrachlorobis (1H-indazole)ruthenate(III)], is the most clinically advanced ruthenium-based therapeutic. As of November 2021, [[BOLD-100]] was being tested in a Phase 1b clinical trial in patients with advanced gastrointestinal cancers in combination with the chemotherapy regimen [[FOLFOX]].<ref name = "NCT04421820">{{ClinicalTrialsGov| NCT04421820|BOLD-100 in combination with FOLFOX for the treatment of advanced solid tumours.}}</ref>
===NAMI===
[[File:BOLD-100-Na.tif|thumb|Chemical structure of sodium trans-[tetrachlorobis (1H-indazole)ruthenate(III)] ([[BOLD-100]])]]
NAMI {Na[''trans''-RuCl<sub>4</sub>](DMSO)(imida)]} and [[NAMI-A]] {H<sub>2</sub>Im[''trans''-RuCl<sub>4</sub>(DMSO)HIm[imidH] are salts that were investigated as anti-cancer drugs.<ref name="seven"/> NAMI-A is considered a [[pro-drug]] and is inactive at physiological pH of 7.4.<ref name="ana"/> Cancer cells generally contain a lower oxygen concentration as well as higher levels of [[glutathione]] and a lower pH than normal tissues creating a [[redox|reducing]] environment. Upon entering cancer cells NAMI-A is activated by the reduction of Ru(III) to Ru(II) to form the active anti-cancer agent.{{Citation needed|date=May 2016}}
===KP1019===
[[KP1019]], a salt of ''trans''-tetrachlorobis(indazole)ruthenate(III) were investigated as drugs.<ref name="ti">{{cite journal |doi=10.2174/1381612033454180 |title=Recent Developments in the Field of Tumor-Inhibiting Metal Complexes |year=2003 |last1=Galanski |first1=M. |last2=Arion |first2=V. |last3=Jakupec |first3=M. |last4=Keppler |first4=B. |journal=Current Pharmaceutical Design |volume=9 |issue=25 |pages=2078–89 |pmid=14529417|s2cid=9170949 }}</ref>  KP1019 has an [[Octahedral molecular geometry|octahedral structure]] with two ''trans'' N-donor [[indazole]] and four [[chloride]] [[ligand]]s in the equatorial plane.<ref name="seksogtyve">{{cite journal |doi=10.1002/(SICI)1099-0682(199909)1999:9<1551::AID-EJIC1551>3.0.CO;2-7 |title=Synthesis of Tumor-Inhibiting Complex Salts Containing the Anion ''trans''-Tetrachlorobis(indazole)ruthenate(III) and Crystal Structure of the Tetraphenylphosphonium Salt |year=1999 |last1=Peti |first1=Wolfgang |last2=Pieper |first2=Thomas |last3=Sommer |first3=Martina |last4=Keppler |first4=Bernhard K. |last5=Giester |first5=Gerald |journal=European Journal of Inorganic Chemistry |volume=1999 |issue=9 |pages=1551–5}}</ref><ref name="elleve">{{cite book |doi=10.1007/s10254-002-0001-x |chapter=Tumour-inhibiting platinum complexes—state of the art and future perspectives |year=2003 |last1=Jakupec |first1=M. A. |last2=Galanski |first2=M. |last3=Keppler |first3=B. K. |title=Reviews of Physiology, Biochemistry and Pharmacology |isbn=978-3-540-00228-4 |volume=146 |pages=1–53 |pmid=12605304}}</ref><ref name="nul">{{cite journal |doi=10.1016/j.jinorgbio.2006.02.013 |title=From bench to bedside – preclinical and early clinical development of the anticancer agent indazolium ''trans''-&#91;tetrachlorobis(1''H''-indazole)ruthenate(III)&#93; (KP1019 or FFC14A) |year=2006 |last1=Hartinger |first1=Christian G. |last2=Zorbas-Seifried |first2=Stefanie |last3=Jakupec |first3=Michael A. |last4=Kynast |first4=Bernd |last5=Zorbas |first5=Haralabos |last6=Keppler |first6=Bernhard K. |journal=Journal of Inorganic Biochemistry |volume=100 |issue=5–6 |pages=891–904 |pmid=16603249}}</ref> It has a low [[solubility]] in [[water]], which makes it difficult to transport in the bloodstream. Instead KP1339{{clarify|date=May 2016}} is used as a preparation of KP1019 in clinical trials, since it has a better [[solubility]] as a [[sodium salt]].<ref name="nul" />
[[Protein]]s and other N-donors are good binding partners for KP1019.<ref name="niogtyve">{{cite journal |doi=10.1021/ic048967h |title=Reactions of Potent Antitumor Complex ''trans''-&#91;Ru<sup>III</sup>Cl<sub>4</sub>(indazole)<sub>2</sub>&#93;<sup>−</sup> with a DNA-Relevant Nucleobase and Thioethers: Insight into Biological Action |year=2005 |last1=Egger |first1=Alexander |last2=Arion |first2=Vladimir B. |last3=Reisner |first3=Erwin |last4=Cebrián-Losantos |first4=Berta |last5=Shova |first5=Sergiu |last6=Trettenhahn |first6=Günter |last7=Keppler |first7=Bernhard K. |journal=Inorganic Chemistry |volume=44 |pages=122–32 |pmid=15627368 |issue=1}}</ref><ref name="enogtredve">{{cite journal |doi=10.1007/s007750050074 |title=Binding of ruthenium(III) anti-tumor drugs to human lactoferrin probed by high resolution X-ray crystallographic structure analyses |year=1996 |last1=Smith |first1=Clyde A. |last2=Sutherland-Smith |first2=Andrew J. |last3=Kratz |first3=Felix |last4=Baker |first4=E. N. |last5=Keppler |first5=B. H. |journal=Journal of Biological Inorganic Chemistry |volume=1 |issue=5 |pages=424–31|s2cid=10270542 }}</ref><ref name="treogtredve">{{cite journal |doi=10.1016/S0162-0134(00)00062-3 |title=Studies on the interactions between human serum albumin and ''trans''-indazolium (bisindazole) tetrachlororuthenate(III) |year=2000 |last1=Trynda-Lemiesz |first1=Lilianna |last2=Karaczyn |first2=Aldona |last3=Keppler |first3=Bernhard K |last4=Kozlowski |first4=Henryk |journal=Journal of Inorganic Biochemistry |volume=78 |issue=4 |pages=341–6 |pmid=10857915}}</ref>
Especially [[transferrin]] and [[albumin]] are good binding partners.<ref name="otteogtredve">{{cite journal |doi=10.1039/B508060F |title=Two dimensional separation schemes for investigation of the interaction of an anticancer ruthenium(iii) compound with plasma proteins |year=2005 |last1=Sulyok |first1=M. |last2=Hann |first2=S. |last3=Hartinger |first3=C. G. |last4=Keppler |first4=B. K. |last5=Stingeder |first5=G. |last6=Koellensperger |first6=G. |journal=Journal of Analytical Atomic Spectrometry |volume=20 |issue=9 |pages=856–63}}</ref> The overall method of action for KP1019 needs to be supported further.
[[Tumor|Tumor cells]] have a high requirement of [[iron]], which results in a large concentration of [[transferrin]]. Ru(III) complexes bind to transferrin and are proposed to interfere with iron uptake.<ref name="fyrre">{{cite journal |pmid=8300587 |year=1994 |last1=Kratz |first1=F |last2=Hartmann |first2=M |last3=Keppler |first3=B |last4=Messori |first4=L |title=The binding properties of two antitumor ruthenium(III) complexes to apotransferrin |volume=269 |issue=4 |pages=2581–8 |journal=The Journal of Biological Chemistry|doi=10.1016/S0021-9258(17)41984-3 |doi-access=free }}</ref><ref name="niogfyrre">{{cite journal |doi=10.1039/B309160K |title=Transferrin binding and transferrin-mediated cellular uptake of the ruthenium coordination compound KP1019, studied by means of AAS, ESI-MS and CD spectroscopy |year=2004 |last1=Pongratz |first1=Martina |last2=Schluga |first2=Petra |last3=Jakupec |first3=Michael A. |last4=Arion |first4=Vladimir B. |last5=Hartinger |first5=Christian G. |last6=Allmaier |first6=Günter |last7=Keppler |first7=Bernhard K. |journal=Journal of Analytical Atomic Spectrometry |volume=19 |pages=46–51}}</ref>
===RAPTA===
[[RAPTA]] compounds are ruthenium–arene complexes bearing the 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane ligand.<ref>{{cite journal |doi=10.1021/om200783r |title=Acetal-Functionalized RAPTA Complexes for Conjugation and Labeling |year=2011 |last1=Tan |first1=Yu Qian |last2=Dyson |first2=Paul J. |last3=Ang |first3=Wee Han |journal=Organometallics |volume=30 |issue=21 |pages=5965–71}}</ref> The complex has a [[piano stool geometry]]. The PTA ligand confers water [[solubility]], and the two chloride [[ligands]] are labile.<ref name="four" />  RAPTA compounds  have low general toxicity that apparently reduces the side-effects associated with chemotherapy.<ref name="four"/>
===RAED===
[[Ruthenium]] diamine complexes have been investigated as potential anticancer drugs.<ref name="b">{{cite journal|last1=Morris|first1=Robert E.|last2=Aird|first2=Rhona E.|last3=del Socorro Murdoch|first3=Piedad|last4=Chen|first4=Haimei|last5=Cummings|first5=Jeff|last6=Hughes|first6=Nathan D.|last7=Parsons|first7=Simon|last8=Parkin|first8=Andrew|last9=Boyd|first9=Gary|last10=Jodrell|first10=Duncan I.|last11=Sadler|first11=Peter J.|title=Inhibition of Cancer Cell Growth by Ruthenium(II) Arene Complexes|journal=Journal of Medicinal Chemistry|volume=44|issue=22|year=2001|pages=3616–3621|issn=0022-2623|doi=10.1021/jm010051m|pmid=11606126}}</ref><ref name="Chen 2002">{{cite journal |vauthors=Chen H, Parkinson JA, Parsons S, Coxall RA, Gould RO, Sadler PJ |title=Organometallic ruthenium(II) diamine anticancer complexes: arene-nucleobase stacking and stereospecific hydrogen-bonding in guanine adducts |journal=Journal of the American Chemical Society |volume=124 |issue=12 |pages=3064–82 |year=2002 |pmid=11902898 |doi=10.1021/ja017482e}}</ref> RAED compounds are ruthenium–arene complexes bearing the 1,2-ethylenediamine ligand.
The ruthenium diamine complexes form adducts with [[guanine]].<ref name="a">{{cite journal |vauthors=Chen H, Parkinson JA, Morris RE, Sadler PJ |title=Highly selective binding of organometallic ruthenium ethylenediamine complexes to nucleic acids: novel recognition mechanisms |journal=Journal of the American Chemical Society |volume=125 |issue=1 |pages=173–86 |year=2003 |pmid=12515520 |doi=10.1021/ja027719m}}</ref> Methylation or substitution on en-NH, which prevent the hydrogen bonding, can lead to the loss of cytotoxic activity of the complex toward cancer cell.<ref name="Bugarcic 2009">{{cite journal |vauthors=Bugarcic T, Habtemariam A, Deeth RJ, Fabbiani FP, Parsons S, Sadler PJ |title=Ruthenium(II) arene anticancer complexes with redox-active diamine ligands |journal=Inorganic Chemistry |volume=48 |issue=19 |pages=9444–53 |year=2009 |pmid=19780621 |doi=10.1021/ic9013366}}</ref><ref name="Habtemariam 2006">{{cite journal |vauthors=Habtemariam A, Melchart M, Fernandez R, Parsons S, Oswald ID, Parkin A, Fabbiani FP, Davidson JE, Dawson A, Aird RE, Jodrell DI, Sadler PJ |title=Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands |journal=Journal of Medicinal Chemistry |volume=49 |issue=23 |pages=6858–68 |year=2006 |pmid=17154516 |doi=10.1021/jm060596m}}</ref> The ethylenediamine ligand suppresses reactions of the complex with amino acid residues. The Ru(II) complexes have a higher affinity to DNA in the presence of protein than the Ru(III) compounds, such as [[NAMI-A]].<ref name="Wang 2002">{{cite journal |vauthors=Wang F, Chen H, Parkinson JA, Murdoch Pdel S, Sadler PJ |title=Reactions of a ruthenium(II) arene antitumor complex with cysteine and methionine |journal=Inorganic Chemistry |volume=41 |issue=17 |pages=4509–23 |year=2002 |pmid=12184769 |doi=10.1021/ic025538f }}</ref>
==References==
{{Reflist|30em}}
[[Category:Experimental cancer drugs]]
[[Category:Ruthenium compounds]]