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Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria
Author(s) -
Imstepf Sebastian,
Pierroz Vanessa,
Rubbiani Riccardo,
Felber Michael,
Fox Thomas,
Gasser Gilles,
Alberto Roger
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201511432
Subject(s) - doxorubicin , mitochondrion , rhenium , hela , cytotoxicity , chemistry , apoptosis , programmed cell death , nucleus , cell , biochemistry , microbiology and biotechnology , biophysics , pharmacology , biology , in vitro , chemotherapy , genetics , inorganic chemistry
Doxorubicin, a well‐established chemotherapeutic agent, is known to accumulate in the cell nucleus. By using ICP‐MS, we show that the conjugation of two small organometallic rhenium complexes to this structural motif results in a significant redirection of the conjugates from the nucleus to the mitochondria. Despite this relocation, the two bioconjugates display excellent toxicity toward HeLa cells. In addition, we carried out a preliminarily investigation of aspects of cytotoxicity and present evidence that the conjugates disrupt the mitochondrial membrane potential, are strong inhibitors of human Topoisomerase II, and induce apoptosis. Such derivatives may enhance the therapeutic index of the aggressive parent drug and overcome drug resistance by influencing nuclear and mitochondrial homeostasis.