Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex

Hong-Ke Liu, John Parkinson, Juraj Bella, Fuyi Wang, Peter Sadler

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

The organometallic RuII arene complex [(eta6-tha)Ru(en)Cl]+ (1), where tha= tetrahydroanthracene and en= ethylenediamine, is potently cytotoxic towards cancer cells. We have used a combination of HPLC, ESI-MS, 1D- and 2D-NMR, including [1H, 1H] ROESY, NOESY, [1H, 15N] HSQC (using 15N-1), and [1H, 31P] experiments to elucidate the role of the non-aromatic, bulky rings of tha in adducts with the DNA hexamer d(CGGCCG), since DNA is a potential target for this drug. Reactions of 1 with single-stranded d(CGGCCG) gave rise to ruthenation at each of the three G bases, whereas reactions of the duplex d(CGGCCG)2 with 1 mol equiv. 1 led to exclusive ruthenation of G3 and G6 (and G9, G12) and not G2 (or G8). Addition of a second mol equiv. of 1 gave di-ruthenated adducts (major sites G3/G6, G6/G9, G2/G6), and on reaction with a third mol equiv. tri-ruthenation (G2, G3/G6/G12).The NMR data are indicative of the coordinative binding of Ru-tha specifically to G3 and G6, together with penetrative intercalation of the bulky non-coordinated tha rings B and C of 1′, selectively between two base pairs G3/C10:C4/G9 and G6/C7:C5/G8. Intercalation at GpC base steps by tha has a lower energy penalty compared to intercalation at GpG base steps, thereby allowing accommodation of tha. Monointercalation
of tha reduced the strength of H-bonding between en-NH and GO6. These differences in structural distortions compared to cisplatin induced by the coordinative binding of Ru-tha to GN7 may contribute to the differences in mechanism of action, including protein recognition of the metallated lesions, and lack of cross resistance.

LanguageEnglish
Pages258-270
Number of pages13
JournalChemical Science
Volume1
Issue number2
Early online date11 Jun 2010
DOIs
Publication statusPublished - 2010

Fingerprint

Organometallics
Intercalation
ethylenediamine
DNA
Nuclear magnetic resonance
Cisplatin
Cells
Pharmaceutical Preparations
Proteins
Experiments

Keywords

  • ruthenium complexes
  • nucleotides
  • double-stranded dna
  • minor-groove
  • crystal structure
  • antitumor drugs
  • nmr structures
  • binding

Cite this

Liu, Hong-Ke ; Parkinson, John ; Bella, Juraj ; Wang, Fuyi ; Sadler, Peter. / Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex. In: Chemical Science. 2010 ; Vol. 1, No. 2. pp. 258-270.
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abstract = "The organometallic RuII arene complex [(eta6-tha)Ru(en)Cl]+ (1), where tha= tetrahydroanthracene and en= ethylenediamine, is potently cytotoxic towards cancer cells. We have used a combination of HPLC, ESI-MS, 1D- and 2D-NMR, including [1H, 1H] ROESY, NOESY, [1H, 15N] HSQC (using 15N-1), and [1H, 31P] experiments to elucidate the role of the non-aromatic, bulky rings of tha in adducts with the DNA hexamer d(CGGCCG), since DNA is a potential target for this drug. Reactions of 1 with single-stranded d(CGGCCG) gave rise to ruthenation at each of the three G bases, whereas reactions of the duplex d(CGGCCG)2 with 1 mol equiv. 1 led to exclusive ruthenation of G3 and G6 (and G9, G12) and not G2 (or G8). Addition of a second mol equiv. of 1 gave di-ruthenated adducts (major sites G3/G6, G6/G9, G2/G6), and on reaction with a third mol equiv. tri-ruthenation (G2, G3/G6/G12).The NMR data are indicative of the coordinative binding of Ru-tha specifically to G3 and G6, together with penetrative intercalation of the bulky non-coordinated tha rings B and C of 1′, selectively between two base pairs G3/C10:C4/G9 and G6/C7:C5/G8. Intercalation at GpC base steps by tha has a lower energy penalty compared to intercalation at GpG base steps, thereby allowing accommodation of tha. Monointercalation of tha reduced the strength of H-bonding between en-NH and GO6. These differences in structural distortions compared to cisplatin induced by the coordinative binding of Ru-tha to GN7 may contribute to the differences in mechanism of action, including protein recognition of the metallated lesions, and lack of cross resistance.",
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Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex. / Liu, Hong-Ke; Parkinson, John; Bella, Juraj; Wang, Fuyi; Sadler, Peter.

In: Chemical Science, Vol. 1, No. 2, 2010, p. 258-270.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Penetrative DNA intercalation and G-base selectivity of an organometallic tetrahydroanthracene RuII anticancer complex

AU - Liu, Hong-Ke

AU - Parkinson, John

AU - Bella, Juraj

AU - Wang, Fuyi

AU - Sadler, Peter

PY - 2010

Y1 - 2010

N2 - The organometallic RuII arene complex [(eta6-tha)Ru(en)Cl]+ (1), where tha= tetrahydroanthracene and en= ethylenediamine, is potently cytotoxic towards cancer cells. We have used a combination of HPLC, ESI-MS, 1D- and 2D-NMR, including [1H, 1H] ROESY, NOESY, [1H, 15N] HSQC (using 15N-1), and [1H, 31P] experiments to elucidate the role of the non-aromatic, bulky rings of tha in adducts with the DNA hexamer d(CGGCCG), since DNA is a potential target for this drug. Reactions of 1 with single-stranded d(CGGCCG) gave rise to ruthenation at each of the three G bases, whereas reactions of the duplex d(CGGCCG)2 with 1 mol equiv. 1 led to exclusive ruthenation of G3 and G6 (and G9, G12) and not G2 (or G8). Addition of a second mol equiv. of 1 gave di-ruthenated adducts (major sites G3/G6, G6/G9, G2/G6), and on reaction with a third mol equiv. tri-ruthenation (G2, G3/G6/G12).The NMR data are indicative of the coordinative binding of Ru-tha specifically to G3 and G6, together with penetrative intercalation of the bulky non-coordinated tha rings B and C of 1′, selectively between two base pairs G3/C10:C4/G9 and G6/C7:C5/G8. Intercalation at GpC base steps by tha has a lower energy penalty compared to intercalation at GpG base steps, thereby allowing accommodation of tha. Monointercalation of tha reduced the strength of H-bonding between en-NH and GO6. These differences in structural distortions compared to cisplatin induced by the coordinative binding of Ru-tha to GN7 may contribute to the differences in mechanism of action, including protein recognition of the metallated lesions, and lack of cross resistance.

AB - The organometallic RuII arene complex [(eta6-tha)Ru(en)Cl]+ (1), where tha= tetrahydroanthracene and en= ethylenediamine, is potently cytotoxic towards cancer cells. We have used a combination of HPLC, ESI-MS, 1D- and 2D-NMR, including [1H, 1H] ROESY, NOESY, [1H, 15N] HSQC (using 15N-1), and [1H, 31P] experiments to elucidate the role of the non-aromatic, bulky rings of tha in adducts with the DNA hexamer d(CGGCCG), since DNA is a potential target for this drug. Reactions of 1 with single-stranded d(CGGCCG) gave rise to ruthenation at each of the three G bases, whereas reactions of the duplex d(CGGCCG)2 with 1 mol equiv. 1 led to exclusive ruthenation of G3 and G6 (and G9, G12) and not G2 (or G8). Addition of a second mol equiv. of 1 gave di-ruthenated adducts (major sites G3/G6, G6/G9, G2/G6), and on reaction with a third mol equiv. tri-ruthenation (G2, G3/G6/G12).The NMR data are indicative of the coordinative binding of Ru-tha specifically to G3 and G6, together with penetrative intercalation of the bulky non-coordinated tha rings B and C of 1′, selectively between two base pairs G3/C10:C4/G9 and G6/C7:C5/G8. Intercalation at GpC base steps by tha has a lower energy penalty compared to intercalation at GpG base steps, thereby allowing accommodation of tha. Monointercalation of tha reduced the strength of H-bonding between en-NH and GO6. These differences in structural distortions compared to cisplatin induced by the coordinative binding of Ru-tha to GN7 may contribute to the differences in mechanism of action, including protein recognition of the metallated lesions, and lack of cross resistance.

KW - ruthenium complexes

KW - nucleotides

KW - double-stranded dna

KW - minor-groove

KW - crystal structure

KW - antitumor drugs

KW - nmr structures

KW - binding

UR - http://pubs.rsc.org/en/content/articlehtml/2010/SC/C0SC00175A?page=search

U2 - 10.1039/c0sc00175a

DO - 10.1039/c0sc00175a

M3 - Article

VL - 1

SP - 258

EP - 270

JO - Chemical Science

T2 - Chemical Science

JF - Chemical Science

SN - 2041-6520

IS - 2

ER -