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Anticancer drug impact on DNA – a study by neutron spectroscopy coupled with synchrotron-based FTIR and EXAFS

DOI: 10.1039/C8CP05881D DOI Help

Authors: Ana L. M. Batista De Carvalho (University of Coimbra) , Adriana P. Mamede (University of Coimbra) , Asha Dopplapudi (ISIS Facility) , Victoria Garcia Sakai (ISIS Facility) , James Doherty (Diamond Light Source; University of Manchester) , Mark Frogley (Diamond Light Source) , Gianfelice Cinque (Diamond Light Source) , Peter Gardner (University of Manchester) , Diego Gianolio (Diamond Light Source) , Luis A. E. Batista De Carvalho (University of Coimbra) , M. Paula M. Marques (University of Coimbra)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Physical Chemistry Chemical Physics , VOL 205

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 14895 , 16058

Abstract: Complementary structural and dynamical information on drug–DNA interplay has been achieved at a molecular level, for Pt/Pd-drugs, allowing a better understanding of their pharmacodynamic profile which is crucial for the development of improved chemotherapeutic agents. The interaction of two cisplatin-like dinuclear Pt(II) and Pd(II) complexes with DNA was studied through a multidisciplinary experimental approach, using quasi-elastic neutron scattering (QENS) techniques coupled with synchrotron-based extended X-ray absorption fine structure (SR-EXAFS) and Fourier-Transform Infrared Spectroscopy-Attenuated Total Reflectance (SR-FTIR-ATR). DNA extracted from drug-exposed human triple negative breast cancer cells (MDA-MB-231) was used, with a view to evaluate the effect of the unconventional antineoplastic agents on this low prognosis type of cancer. The drug impact on DNA's dynamical profile, via its hydration layer, was provided by QENS, a drug-triggered enhanced mobility having been revealed. Additionally, an onset of anharmonicity was detected for dehydrated DNA, at room temperature. Far- and mid-infrared measurements allowed the first simultaneous detection of the drugs and their primary pharmacological target, as well as the drug-prompted changes in DNA's conformation that mediate cytotoxicity. The local environment of the absorbing Pd(II) and Pt(II) centers in the drugs’ adducts with adenine, guanine and glutathione was attained by EXAFS.

Subject Areas: Chemistry, Medicine

Instruments: B18-Core EXAFS , B22-Multimode InfraRed imaging And Microspectroscopy