Controlling Ligand Substitution Reactions of Organometallic Complexes: Tuning Cancer Cell Cytotoxicity
Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other s...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 51; pp. 18269 - 18274 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
20.12.2005
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type $[(\eta^6-arene)Ru(ethylenediamine)(X)]^{n+}$. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. |
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| AbstractList | Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [(eta6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [(eta6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [({eta}6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents.[PUBLICATION ABSTRACT] Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional “piano-stool” ruthenium(II) arene complexes of the type [(η 6 -arene)Ru(ethylenediamine)(X)] n + . A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H 2 O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional “piano-stool” ruthenium(II) arene complexes of the type [(η 6 -arene)Ru(ethylenediamine)(X)] n + . A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H 2 O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. anticancer bioorganometallic hydrolysis kinetics ruthenium complexes Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type $[(\eta^6-arene)Ru(ethylenediamine)(X)]^{n+}$. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [( eta super(6)-arene)Ru(ethylenediamine)(X)] super(n) super(+). A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H sub(2)O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. Organometallic compounds offer broad scope for the design of therapeutic agents, but this avenue has yet to be widely explored. A key concept in the design of anticancer complexes is optimization of chemical reactivity to allow facile attack on the target site (e.g., DNA) yet avoid attack on other sites associated with unwanted side effects. Here, we consider how this result can be achieved for monofunctional "piano-stool" ruthenium(II) arene complexes of the type [(eta6-arene)Ru(ethylenediamine)(X)]n+. A potentially important activation mechanism for reactions with biomolecules is hydrolysis. Density functional calculations suggested that aquation (substitution of X by H2O) occurs by means of a concerted ligand interchange mechanism. We studied the kinetics and equilibria for hydrolysis of 21 complexes, containing, as X, halides and pseudohalides, pyridine (py) derivatives, and a thiolate, together with benzene (bz) or a substituted bz as arene, using UV-visible spectroscopy, HPLC, and electrospray MS. The x-ray structures of six complexes are reported. In general, complexes that hydrolyze either rapidly {e.g., X = halide [arene = hexamethylbenzene (hmb)]} or moderately slowly [e.g., X = azide, dichloropyridine (arene = hmb)] are active toward A2780 human ovarian cancer cells, whereas complexes that do not aquate (e.g., X = py) are inactive. An intriguing exception is the X = thiophenolate complex, which undergoes little hydrolysis and appears to be activated by a different mechanism. The ability to tune the chemical reactivity of this class of organometallic ruthenium arene compounds should be useful in optimizing their design as anticancer agents. |
| Author | Iain D. H. Oswald Parsons, Simon Halpern, Jack Patricia Lozano-Casal Rhona Aird Robert J. Deeth Francesca P. A. Fabbiani Fernández, Rafael Michael Melchart Duncan I. Jodrell Sadler, Peter J. Sylvie Guichard Wang, Fuyi Erwin P. L. van der Geer Abraha Habtemariam |
| AuthorAffiliation | School of Chemistry, University of Edinburgh, West Mains Road, EH9 3JJ Edinburgh, United Kingdom; † Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom; and ‡ CRUK Pharmacology and Drug Development Team, University of Edinburgh Cancer Research Centre, Cancer Research UK Oncology Unit, Crewe Road South, EH4 2XR Edinburgh, United Kingdom |
| AuthorAffiliation_xml | – name: School of Chemistry, University of Edinburgh, West Mains Road, EH9 3JJ Edinburgh, United Kingdom; † Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom; and ‡ CRUK Pharmacology and Drug Development Team, University of Edinburgh Cancer Research Centre, Cancer Research UK Oncology Unit, Crewe Road South, EH4 2XR Edinburgh, United Kingdom |
| Author_xml | – sequence: 1 givenname: Fuyi surname: Wang fullname: Wang, Fuyi – sequence: 2 fullname: Abraha Habtemariam – sequence: 3 fullname: Erwin P. L. van der Geer – sequence: 4 givenname: Rafael surname: Fernández fullname: Fernández, Rafael – sequence: 5 fullname: Michael Melchart – sequence: 6 fullname: Robert J. Deeth – sequence: 7 fullname: Rhona Aird – sequence: 8 fullname: Sylvie Guichard – sequence: 9 fullname: Francesca P. A. Fabbiani – sequence: 10 fullname: Patricia Lozano-Casal – sequence: 11 fullname: Iain D. H. Oswald – sequence: 12 fullname: Duncan I. Jodrell – sequence: 13 givenname: Simon surname: Parsons fullname: Parsons, Simon – sequence: 14 givenname: Peter J. surname: Sadler fullname: Sadler, Peter J. – sequence: 15 givenname: Jack surname: Halpern fullname: Halpern, Jack |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16352726$$D View this record in MEDLINE/PubMed |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Abbreviations: bip, biphenyl; bz, benzene; dcp, 3,5-dichloropyridine; dfp, 3,5-difluoropyridine; dha, dihydroanthracene; en, ethylenediamine; ESI-MS, electrospray ionization MS; hmb, hexamethylbenzene; ind, indan; pic, 3-picoline (3-methylpyridine); pcp, p-cyanopyridine; p-cym, p-cymene; py, pyridine; SPh, thiophenolate; tha, tetrahydroanthracene; UV-Vis, UV-visible. Author contributions: F.W., D.I.J., and P.J.S. designed research; F.W., A.H., E.P.L.v.d.G., R.F., M.M., R.J.D., R.A., S.G., F.P.A.F., P.L.-C., I.D.H.O., and S.P. performed research; F.W., A.H., E.P.L.v.d.G., R.J.D., R.A., S.G., F.P.A.F., P.L.-C., I.D.H.O., D.I.J., S.P., and P.J.S. analyzed data; and F.W., R.J.D., S.P., and P.J.S. wrote the paper. Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved October 27, 2005 This paper was submitted directly (Track II) to the PNAS office. To whom correspondence should be addressed. E-mail: p.j.sadler@ed.ac.uk. Conflict of interest statement: University of Edinburgh has submitted patent applications relating to the compounds used in this study for which an exclusive license has been granted to Oncosense Ltd. Data deposition: The atomic coordinates have been deposited in the Cambridge Structural Database, Cambridge Crystallographic Data Centre, Cambridge CB2 1EZ, United Kingdom (CSD reference nos. 288192–288197). The x-ray crystallographic data for complexes 1, 3, 5, 9, 11, and 19 can be found in Data Sets 1–6, which are published as supporting information on the PNAS web site. |
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| SubjectTerms | Adducts Antineoplastic Agents - chemistry Antineoplastic Agents - toxicity Antineoplastics Arene Benzene Cancer Cell Line, Tumor Cell Survival - drug effects Chemical reactions Chemistry Chlorides Cytotoxicity Design DNA Drug Design Female Guanosine Monophosphate - chemistry Guanosine Monophosphate - metabolism Half lives Halides Humans Hydrolysis Inhibitory Concentration 50 Kinetics Ligands Liquid chromatography Molecular Structure Organometallic Compounds - chemistry Organometallic Compounds - toxicity Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Pharmacology Physical Sciences Ruthenium Ruthenium - chemistry Ruthenium - toxicity |
| Title | Controlling Ligand Substitution Reactions of Organometallic Complexes: Tuning Cancer Cell Cytotoxicity |
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