title: Insights into the structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives.
abstract: The structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives are studied, including interactions with telomeric- and genomic-like DNA sequences, the pKa of their diaqua species, structural properties obtained from DFT calculations and resonant X-ray emission spectroscopy. The binding modes of the compounds to telomeric sequences were elucidated, showing no major differences with conventional cis-platinum(II) complexes like cisplatin, supporting that the cis-square planar geometry governs the binding of small Pt(II) complexes to G4 structures. Double-stranded DNA platination kinetics and acid-base constants of the diaqua species of the compounds were measured and compared, highlighting a strong steric dependence of the DNA-binding kinetics, but independent to stereoisomerism. Structural features of the compounds are discussed on the basis of dispersion-corrected DFT, showing that the most active series presents conformers for which the platinum atom is well devoid of steric hindrance. If reactivity indices derived from conceptual DFT do not show evidences for different reactivity between the compounds, RXES experiments provide new insight into the availability of platinum orbitals for binding to nucleophiles.
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Université Libre de Bruxelles, Campus Plaine CP205/5, Bd du Triomphe, 1050, Brussels, Belgium, giberger@ulb.ac.be.
authors.forename: Gilles
authors.initials: G
authors.lastname: Berger
authors.forename: Luca
authors.initials: L
authors.lastname: Fusaro
authors.forename: Michel
authors.initials: M
authors.lastname: Luhmer
authors.forename: Joanna
authors.initials: J
authors.lastname: Czapla-Masztafiak
authors.forename: Ewelina
authors.initials: E
authors.lastname: Lipiec
authors.forename: Jakub
authors.initials: J
authors.lastname: Szlachetko
authors.forename: Yves
authors.initials: Y
authors.lastname: Kayser
authors.forename: Daniel L A
authors.initials: DL
authors.lastname: Fernandes
authors.forename: Jacinto
authors.initials: J
authors.lastname: Sá
authors.forename: François
authors.initials: F
authors.lastname: Dufrasne
authors.forename: Sophie
authors.initials: S
authors.lastname: Bombard
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes / Q000187:drug effects; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006843:Hydrocarbons, Chlorinated; D009944:Organoplatinum Compounds