Induced fit recognition of DNA by organometallic complexes with dynamic stereogenic centres

J.A. Parkinson, H.M. Chen, O. Novakova, J. Bella, F. Wang, A. Dawson, R.O. Gould, S. Parsons, V. Brabec, P.J. Sadler

Research output: Contribution to journalArticle

100 Citations (Scopus)

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 η6-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((η6-biphenyl)RuCl(en))2-(CH2)6]2 + (3, en = ethylenediamine) was elucidated by studies of the half unit [(η6-biphenyl)RuCl(Et-en)]+ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated and diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t½ ≈ 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the configurations are more stable than (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31°) of plasmid DNA, twice that of mononuclear 2 (14°), 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.
LanguageEnglish
Pages14623-14628
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume100
Issue number25
DOIs
Publication statusPublished - 2003

Fingerprint

Organometallics
DNA
ethylenediamine
Intercalation
Plasmids
X rays
Molecular recognition
Stereochemistry
Ethidium
Crystallography
Guanine
Pharmaceutical Preparations
Cisplatin
Nuclear magnetic resonance spectroscopy
Nuclear magnetic resonance
RNA
Water
diphenyl

Keywords

  • organometallic complexes
  • dynamic stereogenic centres

Cite this

Parkinson, J.A. ; Chen, H.M. ; Novakova, O. ; Bella, J. ; Wang, F. ; Dawson, A. ; Gould, R.O. ; Parsons, S. ; Brabec, V. ; Sadler, P.J. / Induced fit recognition of DNA by organometallic complexes with dynamic stereogenic centres. In: Proceedings of the National Academy of Sciences . 2003 ; Vol. 100, No. 25. pp. 14623-14628.
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Parkinson, JA, Chen, HM, Novakova, O, Bella, J, Wang, F, Dawson, A, Gould, RO, Parsons, S, Brabec, V & Sadler, PJ 2003, 'Induced fit recognition of DNA by organometallic complexes with dynamic stereogenic centres' Proceedings of the National Academy of Sciences , vol. 100, no. 25, pp. 14623-14628. https://doi.org/10.1073/pnas.2434016100

Induced fit recognition of DNA by organometallic complexes with dynamic stereogenic centres. / Parkinson, J.A.; Chen, H.M.; Novakova, O.; Bella, J.; Wang, F.; Dawson, A.; Gould, R.O.; Parsons, S.; Brabec, V.; Sadler, P.J.

In: Proceedings of the National Academy of Sciences , Vol. 100, No. 25, 2003, p. 14623-14628.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Induced fit recognition of DNA by organometallic complexes with dynamic stereogenic centres

AU - Parkinson, J.A.

AU - Chen, H.M.

AU - Novakova, O.

AU - Bella, J.

AU - Wang, F.

AU - Dawson, A.

AU - Gould, R.O.

AU - Parsons, S.

AU - Brabec, V.

AU - Sadler, P.J.

PY - 2003

Y1 - 2003

N2 - Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by η6-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((η6-biphenyl)RuCl(en))2-(CH2)6]2 + (3, en = ethylenediamine) was elucidated by studies of the half unit [(η6-biphenyl)RuCl(Et-en)]+ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated and diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t½ ≈ 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the configurations are more stable than (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31°) of plasmid DNA, twice that of mononuclear 2 (14°), 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.

AB - Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by η6-arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [((η6-biphenyl)RuCl(en))2-(CH2)6]2 + (3, en = ethylenediamine) was elucidated by studies of the half unit [(η6-biphenyl)RuCl(Et-en)]+ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated and diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t½ ≈ 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the configurations are more stable than (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31°) of plasmid DNA, twice that of mononuclear 2 (14°), 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.

KW - organometallic complexes

KW - dynamic stereogenic centres

U2 - 10.1073/pnas.2434016100

DO - 10.1073/pnas.2434016100

M3 - Article

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EP - 14628

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

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