Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers.
Identifieur interne : 003211 ( Main/Exploration ); précédent : 003210; suivant : 003212Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers.
Auteurs : Haimei Chen [Royaume-Uni] ; John A. Parkinson ; Olga Nováková ; Juraj Bella ; Fuyi Wang ; Alice Dawson ; Robert Gould ; Simon Parsons ; Viktor Brabec ; Peter J. SadlerSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2003.
Descripteurs français
- KwdFr :
- ADN (), ADN superhélicoïdal (), Antinéoplasiques (pharmacologie), Cinétique, Cisplatine (pharmacologie), Conformation d'acide nucléique, Conformation moléculaire, Cristallographie aux rayons X, DNA-directed RNA polymerases (), Dichroïsme circulaire, Données de séquences moléculaires, Facteurs temps, Guanine (), Guanine (analogues et dérivés), Modèles chimiques, Modèles moléculaires, Plasmides (métabolisme), Réactifs réticulants (pharmacologie), Spectroscopie par résonance magnétique, Stéréoisomérie, Séquence nucléotidique, Transcription génétique, Éthidium (pharmacologie).
- MESH :
- analogues et dérivés : Guanine.
- métabolisme : Plasmides.
- pharmacologie : Antinéoplasiques, Cisplatine, Réactifs réticulants, Éthidium.
- ADN, ADN superhélicoïdal, Cinétique, Conformation d'acide nucléique, Conformation moléculaire, Cristallographie aux rayons X, DNA-directed RNA polymerases, Dichroïsme circulaire, Données de séquences moléculaires, Facteurs temps, Guanine, Modèles chimiques, Modèles moléculaires, Spectroscopie par résonance magnétique, Stéréoisomérie, Séquence nucléotidique, Transcription génétique.
English descriptors
- KwdEn :
- Antineoplastic Agents (pharmacology), Base Sequence, Circular Dichroism, Cisplatin (pharmacology), Cross-Linking Reagents (pharmacology), Crystallography, X-Ray, DNA (chemistry), DNA, Superhelical (chemistry), DNA-Directed RNA Polymerases (chemistry), Ethidium (pharmacology), Guanine (analogs & derivatives), Guanine (chemistry), Kinetics, Magnetic Resonance Spectroscopy, Models, Chemical, Models, Molecular, Molecular Conformation, Molecular Sequence Data, Nucleic Acid Conformation, Plasmids (metabolism), Stereoisomerism, Time Factors, Transcription, Genetic.
- MESH :
- chemical , analogs & derivatives : Guanine.
- chemical , chemistry : DNA, DNA, Superhelical, DNA-Directed RNA Polymerases, Guanine.
- chemical , pharmacology : Antineoplastic Agents, Cisplatin, Cross-Linking Reagents, Ethidium.
- metabolism : Plasmids.
- Base Sequence, Circular Dichroism, Crystallography, X-Ray, Kinetics, Magnetic Resonance Spectroscopy, Models, Chemical, Models, Molecular, Molecular Conformation, Molecular Sequence Data, Nucleic Acid Conformation, Stereoisomerism, Time Factors, Transcription, Genetic.
Abstract
Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by eta 6-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((eta 6-biphenyl)RuCl(en))2-(CH2)6]2 + (3, en = ethylenediamine) was elucidated by studies of the half unit [(eta 6-biphenyl)RuCl(Et-en)]+ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated RRu*RN* and SRu*RN* diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t(1/2) approximately 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the RRu*RN* configurations are more stable than SRu*RN* (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to SRu*RN* diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31 degrees) of plasmid DNA, twice that of mononuclear 2 (14 degrees), and effectively inhibited DNA-directed RNA synthesis in vitro. This dinuclear complex gave rise to interstrand cross-links on a 213-bp plasmid fragment with efficiency similar to bifunctional cisplatin, and to 1,3-GG interstrand and 1,2-GG and 1,3-GTG intrastrand cross-links on site-specifically ruthenated 20-mers. Complex 3 blocked intercalation of ethidium considerably more than mononuclear 2. The concept of induced-fit recognition of DNA by organometallic complexes containing dynamic stereogenic centers via dynamic epimerization, intercalation, and cross-linking may be useful in the design of anticancer drugs.
DOI: 10.1073/pnas.2434016100
PubMed: 14657383
Affiliations:
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Parkinson</name></author><author><name sortKey="Novakova, Olga" sort="Novakova, Olga" uniqKey="Novakova O" first="Olga" last="Nováková">Olga Nováková</name></author><author><name sortKey="Bella, Juraj" sort="Bella, Juraj" uniqKey="Bella J" first="Juraj" last="Bella">Juraj Bella</name></author><author><name sortKey="Wang, Fuyi" sort="Wang, Fuyi" uniqKey="Wang F" first="Fuyi" last="Wang">Fuyi Wang</name></author><author><name sortKey="Dawson, Alice" sort="Dawson, Alice" uniqKey="Dawson A" first="Alice" last="Dawson">Alice Dawson</name></author><author><name sortKey="Gould, Robert" sort="Gould, Robert" uniqKey="Gould R" first="Robert" last="Gould">Robert Gould</name></author><author><name sortKey="Parsons, Simon" sort="Parsons, Simon" uniqKey="Parsons S" first="Simon" last="Parsons">Simon Parsons</name></author><author><name sortKey="Brabec, Viktor" sort="Brabec, Viktor" uniqKey="Brabec V" first="Viktor" last="Brabec">Viktor Brabec</name></author><author><name sortKey="Sadler, Peter J" sort="Sadler, Peter J" uniqKey="Sadler P" first="Peter J" last="Sadler">Peter J. 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Parkinson</name></author><author><name sortKey="Novakova, Olga" sort="Novakova, Olga" uniqKey="Novakova O" first="Olga" last="Nováková">Olga Nováková</name></author><author><name sortKey="Bella, Juraj" sort="Bella, Juraj" uniqKey="Bella J" first="Juraj" last="Bella">Juraj Bella</name></author><author><name sortKey="Wang, Fuyi" sort="Wang, Fuyi" uniqKey="Wang F" first="Fuyi" last="Wang">Fuyi Wang</name></author><author><name sortKey="Dawson, Alice" sort="Dawson, Alice" uniqKey="Dawson A" first="Alice" last="Dawson">Alice Dawson</name></author><author><name sortKey="Gould, Robert" sort="Gould, Robert" uniqKey="Gould R" first="Robert" last="Gould">Robert Gould</name></author><author><name sortKey="Parsons, Simon" sort="Parsons, Simon" uniqKey="Parsons S" first="Simon" last="Parsons">Simon Parsons</name></author><author><name sortKey="Brabec, Viktor" sort="Brabec, Viktor" uniqKey="Brabec V" first="Viktor" last="Brabec">Viktor Brabec</name></author><author><name sortKey="Sadler, Peter J" sort="Sadler, Peter J" uniqKey="Sadler P" first="Peter J" last="Sadler">Peter J. Sadler</name></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><imprint><date when="2003" type="published">2003</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic Agents (pharmacology)</term><term>Base Sequence</term><term>Circular Dichroism</term><term>Cisplatin (pharmacology)</term><term>Cross-Linking Reagents (pharmacology)</term><term>Crystallography, X-Ray</term><term>DNA (chemistry)</term><term>DNA, Superhelical (chemistry)</term><term>DNA-Directed RNA Polymerases (chemistry)</term><term>Ethidium (pharmacology)</term><term>Guanine (analogs & derivatives)</term><term>Guanine (chemistry)</term><term>Kinetics</term><term>Magnetic Resonance Spectroscopy</term><term>Models, Chemical</term><term>Models, Molecular</term><term>Molecular Conformation</term><term>Molecular Sequence Data</term><term>Nucleic Acid Conformation</term><term>Plasmids (metabolism)</term><term>Stereoisomerism</term><term>Time Factors</term><term>Transcription, Genetic</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN ()</term><term>ADN superhélicoïdal ()</term><term>Antinéoplasiques (pharmacologie)</term><term>Cinétique</term><term>Cisplatine (pharmacologie)</term><term>Conformation d'acide nucléique</term><term>Conformation moléculaire</term><term>Cristallographie aux rayons X</term><term>DNA-directed RNA polymerases ()</term><term>Dichroïsme circulaire</term><term>Données de séquences moléculaires</term><term>Facteurs temps</term><term>Guanine ()</term><term>Guanine (analogues et dérivés)</term><term>Modèles chimiques</term><term>Modèles moléculaires</term><term>Plasmides (métabolisme)</term><term>Réactifs réticulants (pharmacologie)</term><term>Spectroscopie par résonance magnétique</term><term>Stéréoisomérie</term><term>Séquence nucléotidique</term><term>Transcription génétique</term><term>Éthidium (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Guanine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>DNA</term><term>DNA, Superhelical</term><term>DNA-Directed RNA Polymerases</term><term>Guanine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term><term>Cisplatin</term><term>Cross-Linking Reagents</term><term>Ethidium</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Guanine</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Plasmids</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Plasmides</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term><term>Cisplatine</term><term>Réactifs réticulants</term><term>Éthidium</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Base Sequence</term><term>Circular Dichroism</term><term>Crystallography, X-Ray</term><term>Kinetics</term><term>Magnetic Resonance Spectroscopy</term><term>Models, Chemical</term><term>Models, Molecular</term><term>Molecular Conformation</term><term>Molecular Sequence Data</term><term>Nucleic Acid Conformation</term><term>Stereoisomerism</term><term>Time Factors</term><term>Transcription, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ADN</term><term>ADN superhélicoïdal</term><term>Cinétique</term><term>Conformation d'acide nucléique</term><term>Conformation moléculaire</term><term>Cristallographie aux rayons X</term><term>DNA-directed RNA polymerases</term><term>Dichroïsme circulaire</term><term>Données de séquences moléculaires</term><term>Facteurs temps</term><term>Guanine</term><term>Modèles chimiques</term><term>Modèles moléculaires</term><term>Spectroscopie par résonance magnétique</term><term>Stéréoisomérie</term><term>Séquence nucléotidique</term><term>Transcription génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by eta 6-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((eta 6-biphenyl)RuCl(en))2-(CH2)6]2 + (3, en = ethylenediamine) was elucidated by studies of the half unit [(eta 6-biphenyl)RuCl(Et-en)]+ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated RRu*RN* and SRu*RN* diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t(1/2) approximately 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the RRu*RN* configurations are more stable than SRu*RN* (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to SRu*RN* diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31 degrees) of plasmid DNA, twice that of mononuclear 2 (14 degrees), and effectively inhibited DNA-directed RNA synthesis in vitro. This dinuclear complex gave rise to interstrand cross-links on a 213-bp plasmid fragment with efficiency similar to bifunctional cisplatin, and to 1,3-GG interstrand and 1,2-GG and 1,3-GTG intrastrand cross-links on site-specifically ruthenated 20-mers. Complex 3 blocked intercalation of ethidium considerably more than mononuclear 2. The concept of induced-fit recognition of DNA by organometallic complexes containing dynamic stereogenic centers via dynamic epimerization, intercalation, and cross-linking may be useful in the design of anticancer drugs.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Écosse</li></region><settlement><li>Édimbourg</li></settlement><orgName><li>Université d'Édimbourg</li></orgName></list><tree><noCountry><name sortKey="Bella, Juraj" sort="Bella, Juraj" uniqKey="Bella J" first="Juraj" last="Bella">Juraj Bella</name><name sortKey="Brabec, Viktor" sort="Brabec, Viktor" uniqKey="Brabec V" first="Viktor" last="Brabec">Viktor Brabec</name><name sortKey="Dawson, Alice" sort="Dawson, Alice" uniqKey="Dawson A" first="Alice" last="Dawson">Alice Dawson</name><name sortKey="Gould, Robert" sort="Gould, Robert" uniqKey="Gould R" first="Robert" last="Gould">Robert Gould</name><name sortKey="Novakova, Olga" sort="Novakova, Olga" uniqKey="Novakova O" first="Olga" last="Nováková">Olga Nováková</name><name sortKey="Parkinson, John A" sort="Parkinson, John A" uniqKey="Parkinson J" first="John A" last="Parkinson">John A. Parkinson</name><name sortKey="Parsons, Simon" sort="Parsons, Simon" uniqKey="Parsons S" first="Simon" last="Parsons">Simon Parsons</name><name sortKey="Sadler, Peter J" sort="Sadler, Peter J" uniqKey="Sadler P" first="Peter J" last="Sadler">Peter J. Sadler</name><name sortKey="Wang, Fuyi" sort="Wang, Fuyi" uniqKey="Wang F" first="Fuyi" last="Wang">Fuyi Wang</name></noCountry><country name="Royaume-Uni"><region name="Écosse"><name sortKey="Chen, Haimei" sort="Chen, Haimei" uniqKey="Chen H" first="Haimei" last="Chen">Haimei Chen</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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