Journal Article Ppublish
PubMed: 40435581 DOI: 10.1021/acs.inorgchem.5c01882
Excited-State Cis and Trans Pt(IV) Diamine Anticancer Complexes.
Inorg Chem 64(22):11301-11311
Authors: Huayun Shi, Jana Kasparkova, Fortuna Ponte, Hana Kostrhunova, Guy J Clarkson, Emilia Sicilia, Viktor Brabec, Peter J Sadler
Affiliations
- Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen361102, China.
- Department of Biophysics, Faculty of Science, Palacky University, CZ-77900 Olomouc, Czech Republic.
- Institute of Biophysics, Czech Academy of Sciences, CZ-61200 Brno, Czech Republic.
- Department of Chemistry and Chemical Technologies, University of Calabria, via Pietro Bucci, 87036 Arcavacata di Rende , Cs, Italy.
Abstract
Classical structure-activity relationships for square-planar Pt(II) anticancer complexes were based on the activity of cis-[PtCl 2(NH 3) 2] (cisplatin) and inactivity of the trans isomer. Many other families of cis-diamine complexes and analogous octahedral Pt(IV) prodrugs are active. Here, we report the chemical and biological activities of isomeric photoactivatable cis,trans,cis- and all-trans-[Pt(N 3) 2(OH) 2(MNZ) 2] complexes (MNZ = metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole). While both are relatively nontoxic in the ground state, only the all-trans isomer is cytotoxic toward bladder cancer cells on excitation with visible light and under hypoxia. Studies of DNA interstrand cross-links and photocytotoxicity toward wild-type and nucleotide-excision-repair deficient cells suggest that, unlike cisplatin, DNA is not the major target site of these isomers. Differences in photoactivation pathways were also explored using time-dependent DFT calculations. The key differences between the isomers on irradiation are the more rapid photoactivation of the all-trans complex, generation of azidyl radicals, retention of its metronidazole ligands, higher accumulation in cancer cells, binding to DNA, RNA, and proteins, and induction of apoptosis and mitochondrial membrane damages. These findings provide a basis for the design of future photochemotherapeutic platinum anticancer prodrugs.
MeSH
Cells, Metronidazole, Neoplasms, Diamines, Prodrugs, Excision Repair