title: Molecular basis of structure-activity relationships between salphen metal complexes and human telomeric DNA quadruplexes.
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.
authors: CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-29 Brunswick Square, London WC1N 1AX, U.K.
authors: Nancy H
authors: NH
authors: Campbell
authors: Nurul H Abd
authors: NH
authors: Karim
authors: Gary N
authors: GN
authors: Parkinson
authors: Mekala
authors: M
authors: Gunaratnam
authors: Vanessa
authors: V
authors: Petrucci
authors: Alan K
authors: AK
authors: Todd
authors: Ramon
authors: R
authors: Vilar
authors: Stephen
authors: S
authors: Neidle
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003300:Copper; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel; D010655:Phenylenediamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010655:Phenylenediamines; C545695:salphen; D003300:Copper; D009532:Nickel; D019098:Telomerase