Diazido Mixed-Amine Platinum(IV) Anticancer Complexes Activatable by Visible-Light Form Novel DNA Adducts

0394801 - BFÚ 2014 RIV DE eng J - Journal Article
Zhao, Y. - Woods, J. - Farrer, N.J. - Robinson, K.S. - Prachařová, J. - Kašpárková, J. - Nováková, Olga - Li, H.L. - Salassa, L. - Pizarro, A.M. - Clarkson, G.J. - Song, L.J. - Brabec, Viktor - Sadler, P. J.
Diazido Mixed-Amine Platinum(IV) Anticancer Complexes Activatable by Visible-Light Form Novel DNA Adducts.
Chemistry - A European Journal. Roč. 19, č. 29 (2013), s. 9578-9591. ISSN 0947-6539. E-ISSN 1521-3765
R&D Projects: GA ČR(CZ) GAP301/10/0598
Grant - others:GA AV(CZ) M200041201
Institutional support: RVO:68081707
Keywords : antitumor agents * DNA binding * medicinal chemistry
Subject RIV: BO - Biophysics
Impact factor: 5.696, year: 2013

Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable Pt-IV prodrugs offer the potential of targeted drug release and new mechanisms of action. We report the synthesis, X-ray crystallographic and spectroscopic properties of photoactivatable diazido complexes trans,trans,trans-[Pt(N-3)(2)(OH)(2)(MA)(Py)] (1; MA=methylamine, Py=pyridine) and trans,trans,trans-[Pt(N-3)(2)(OH)(2)(MA)(Tz)] (2; Tz=thiazole), and interpret their photophysical properties by TD-DFT modelling. The orientation of the azido groups is highly dependent on Hbonding and crystal packing, as shown by polymorphs 1p and 1q. Complexes 1 and 2 are stable in the dark towards hydrolysis and glutathione reduction, but undergo rapid photoreduction with UVA or blue light with minimal amine photodissociation. They are over an order of magnitude more potent towards HaCaT keratinocytes, A2780 ovarian, and OE19 oesophageal carcinoma cells than cisplatin and show particular potency towards cisplatin-resistant human ovarian cancer cells (A2780cis).
Permanent Link: http://hdl.handle.net/11104/0222991