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

DOI: 10.1021/jm201140v DOI Help
PMID: 22112241 PMID Help

Authors: Nancy H. Campbell (The School of Pharmacy, University of London) , Nurul H. Abd Karim (Imperial College London) , Gary N. Parkinson (The School of Pharmacy, University of London) , Mekala Gunaratnam (The School of Pharmacy, University of London) , Vanessa Petrucci (The School of Pharmacy, University of London) , Alan K. Todd (The School of Pharmacy, University of London) , Ramon Vilar (Imperial College London) , Stephen Neidle (The School of Pharmacy, University of London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 55 (1)

State: Published (Approved)
Published: November 2011

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

Journal Keywords: Cell; Tumor; Cell; Coordination; Copper; Crystallography; X-Ray; Drug; Antitumor; G-Quadruplexes; Humans; Models; Molecular; Nickel; Phenylenediamines; Structure-Activity; Telomerase; Telomere

Subject Areas: Medicine, Chemistry, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 02/12/2011 13:38

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)