Molecular basis of structure-activity relationships between salphen metal complexes and human telomeric DNA quadruplexes

Nancy H. Campbell, Nurul Huda Abd Karim, Gary N. Parkinson, Mekala Gunaratnam, Vanessa Petrucci, Alan K. Todd, Ramon Vilar, Stephen Neidle

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

The first X-ray crystal structures of nickel(II) and copper(II) salphen metal complexes bound to a quadruplex DNA are presented. Two structures have been determined and show that these salphen-metal complexes bind to human telomeric quadruplexes by end-stacking, with the metal in each case almost in line with the potassium ion channel. Quadruplex and duplex DNA binding is presented for these two and other related salphen complexes, all with side-chains terminating in pyrrolidino end-groups and differing patterns of substitution on the salphen core. The crystal structures are able to provide rationalizations for the structure-activity data, and in particular for the superior quadruplex-binding of the nickel complexes compared to that of the copper-containing ones. The complexes show significant antiproliferative activity for the compounds in a panel of cancer cell lines. They also show telomerase inhibitory activity in the telomerase TRAP-LIG assay.

Original languageEnglish
Pages (from-to)209-222
Number of pages14
JournalJournal of Medicinal Chemistry
Volume55
Issue number1
DOIs
Publication statusPublished - 12 Jan 2012
Externally publishedYes

Fingerprint

G-Quadruplexes
Coordination Complexes
Structure-Activity Relationship
Molecular Structure
Telomerase
Nickel
Copper
Potassium Channels
Metals
X-Rays
Cell Line
salphen
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Molecular basis of structure-activity relationships between salphen metal complexes and human telomeric DNA quadruplexes. / Campbell, Nancy H.; Abd Karim, Nurul Huda; Parkinson, Gary N.; Gunaratnam, Mekala; Petrucci, Vanessa; Todd, Alan K.; Vilar, Ramon; Neidle, Stephen.

In: Journal of Medicinal Chemistry, Vol. 55, No. 1, 12.01.2012, p. 209-222.

Research output: Contribution to journalArticle

Campbell, Nancy H. ; Abd Karim, Nurul Huda ; Parkinson, Gary N. ; Gunaratnam, Mekala ; Petrucci, Vanessa ; Todd, Alan K. ; Vilar, Ramon ; Neidle, Stephen. / Molecular basis of structure-activity relationships between salphen metal complexes and human telomeric DNA quadruplexes. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 1. pp. 209-222.
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