The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding

The monofunctional platinum complex cis-[Pt(NH[subscript 3])[subscript 2]Cl(Am)][superscript +], also known as phenanthriplatin, where Am is the N-heterocyclic base phenanthridine, has promising anticancer activity. Unlike bifunctional compounds such as cisplatin, phenanthriplatin can form only one...

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Main Authors: Lippard, Stephen J., Johnstone, Timothy
Other Authors: Massachusetts Institute of Technology. Department of Chemistry
Format: Article
Language:en_US
Published: American Chemical Society (ACS) 2015
Online Access:http://hdl.handle.net/1721.1/95480
https://orcid.org/0000-0002-2693-4982
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author Lippard, Stephen J.
Johnstone, Timothy
author2 Massachusetts Institute of Technology. Department of Chemistry
author_facet Massachusetts Institute of Technology. Department of Chemistry
Lippard, Stephen J.
Johnstone, Timothy
author_sort Lippard, Stephen J.
collection MIT
description The monofunctional platinum complex cis-[Pt(NH[subscript 3])[subscript 2]Cl(Am)][superscript +], also known as phenanthriplatin, where Am is the N-heterocyclic base phenanthridine, has promising anticancer activity. Unlike bifunctional compounds such as cisplatin, phenanthriplatin can form only one covalent bond to DNA. Another distinguishing feature is that phenanthriplatin is chiral. Rotation about the Pt–N bond of the phenanthridine ligand racemizes the complex, and the question arises as to whether this process is sufficiently slow under physiological conditions to impact its DNA-binding properties. Here we present the results of NMR spectroscopic, X-ray crystallographic, molecular dynamics, and density functional theoretical investigations of diastereomeric phenanthriplatin analogs in order to probe the internal dynamics of phenanthriplatin. These results reveal that phenanthriplatin rapidly racemizes under physiological conditions. The information also facilitated the interpretation of the NMR spectra of small molecule models of phenanthriplatin-platinated DNA. These studies indicate, inter alia, that one diastereomeric form of the complexes cis-[Pt(NH[subscript 3])[subscript 2](Am)(R-Gua)][superscript 2+], where R-Gua is 9-methyl- or 9-ethylguanine, is preferred over the other, the origin of which stems from an intramolecular interaction between the carbonyl oxygen of the platinated guanine base and a cis-coordinated ammine. The relevance of this finding to the DNA-damaging properties of phenanthriplatin and its biological activity is discussed.
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spelling mit-1721.1/954802022-10-01T11:30:01Z The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding Lippard, Stephen J. Johnstone, Timothy Massachusetts Institute of Technology. Department of Chemistry Lippard, Stephen J. Johnstone, Timothy The monofunctional platinum complex cis-[Pt(NH[subscript 3])[subscript 2]Cl(Am)][superscript +], also known as phenanthriplatin, where Am is the N-heterocyclic base phenanthridine, has promising anticancer activity. Unlike bifunctional compounds such as cisplatin, phenanthriplatin can form only one covalent bond to DNA. Another distinguishing feature is that phenanthriplatin is chiral. Rotation about the Pt–N bond of the phenanthridine ligand racemizes the complex, and the question arises as to whether this process is sufficiently slow under physiological conditions to impact its DNA-binding properties. Here we present the results of NMR spectroscopic, X-ray crystallographic, molecular dynamics, and density functional theoretical investigations of diastereomeric phenanthriplatin analogs in order to probe the internal dynamics of phenanthriplatin. These results reveal that phenanthriplatin rapidly racemizes under physiological conditions. The information also facilitated the interpretation of the NMR spectra of small molecule models of phenanthriplatin-platinated DNA. These studies indicate, inter alia, that one diastereomeric form of the complexes cis-[Pt(NH[subscript 3])[subscript 2](Am)(R-Gua)][superscript 2+], where R-Gua is 9-methyl- or 9-ethylguanine, is preferred over the other, the origin of which stems from an intramolecular interaction between the carbonyl oxygen of the platinated guanine base and a cis-coordinated ammine. The relevance of this finding to the DNA-damaging properties of phenanthriplatin and its biological activity is discussed. National Cancer Institute (U.S.) (Grant CA034992) 2015-02-24T16:05:45Z 2015-02-24T16:05:45Z 2014-01 2013-12 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/95480 Johnstone, Timothy C., and Stephen J. Lippard. “The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding.” Journal of the American Chemical Society 136, no. 5 (February 5, 2014): 2126–2134. © 2014 American Chemical Society https://orcid.org/0000-0002-2693-4982 en_US http://dx.doi.org/10.1021/ja4125115 Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC
spellingShingle Lippard, Stephen J.
Johnstone, Timothy
The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding
title The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding
title_full The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding
title_fullStr The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding
title_full_unstemmed The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding
title_short The Chiral Potential of Phenanthriplatin and Its Influence on Guanine Binding
title_sort chiral potential of phenanthriplatin and its influence on guanine binding
url http://hdl.handle.net/1721.1/95480
https://orcid.org/0000-0002-2693-4982
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