TY - JOUR
T1 - Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines
AU - Havrylyuk, Dmytro
AU - Howerton, Brock S.
AU - Nease, Leona
AU - Parkin, Sean
AU - Heidary, David K.
AU - Glazer, Edith C.
N1 - Publisher Copyright:
© 2018
PY - 2018/8/5
Y1 - 2018/8/5
N2 - 8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2–15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.
AB - 8-Hydroxyquinolines (HQ), including clioquinol, possess cytotoxic properties and are widely used as ligands for metal-based anticancer drug research. The number and identity of substituents on the HQ can have a profound effect on activity for a variety of inorganic compounds. Ruthenium complexes of HQ exhibit radically improved potencies, and operate by a new, currently unknown, mechanism of action. To define structure-activity relationships (SAR), a family of 22 Ru(II) coordination complexes containing mono-, di- and tri-substituted hydroxyquinoline ligands were synthesized and their biological activity evaluated. The complexes exhibited promising cytotoxic activity against a cancer cell line, and the SAR data revealed the 2- and 7-positions as key sites for the incorporation of halogens to improve potency. The Ru(II) complexes potently inhibited translation, as demonstrated by an in-cell translation assay. The effects were seen at 2–15-fold higher concentrations than those required to observe cytotoxicity, suggesting that prevention of protein synthesis may be a primary, but not the exclusive mechanism for the observed cytotoxic activity.
KW - Cancer
KW - Coordination chemistry
KW - Cytotoxic
KW - Ruthenium
KW - Translation
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U2 - 10.1016/j.ejmech.2018.04.044
DO - 10.1016/j.ejmech.2018.04.044
M3 - Article
C2 - 30055464
AN - SCOPUS:85050272144
SN - 0223-5234
VL - 156
SP - 790
EP - 799
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -