Ruthenium anticancer agent KP1019 binds more tightly than NAMI-A to tRNAPhe

Brendan G Dwyer; Emily Johnson; Efren Cazares; Karen L McFarlane Holman; Sarah R Kirk

doi:10.1016/j.jinorgbio.2018.02.019

Ruthenium anticancer agent KP1019 binds more tightly than NAMI-A to tRNA^Phe

J Inorg Biochem. 2018 May:182:177-183. doi: 10.1016/j.jinorgbio.2018.02.019. Epub 2018 Feb 24.

Authors

Brendan G Dwyer¹, Emily Johnson¹, Efren Cazares¹, Karen L McFarlane Holman¹, Sarah R Kirk²

Affiliations

¹ Department of Chemistry, Willamette University, 900 State Street, Salem, Oregon 97301, United States.
² Department of Chemistry, Willamette University, 900 State Street, Salem, Oregon 97301, United States. Electronic address: skirk@willamette.edu.

PMID: 29501978
DOI: 10.1016/j.jinorgbio.2018.02.019

Abstract

The ruthenium-based anticancer agent NAMI-A (ImH[trans-RuCl₄(dmso)(Im)], where Im = imidazole) has been shown to interact with RNA in vivo and in vitro. We hypothesized that the similarly structured drug KP1019 (IndH[trans-RuCl₄(Ind)₂], where Ind = indazole) binds to RNA as well. Fluorescence spectroscopy was employed to assay the interactions between either NAMI-A or KP1019 and tRNA^Phe through an intrinsic fluorophore wybutosine (Y) base and by extrinsic displacement of the intercalating agent ethidium bromide. In both the intrinsic Y-base and extrinsic ethidium bromide studies, KP1019 exhibited tighter binding to phenylalanine-specific tRNA (tRNA^Phe) than NAMI-A. In the ethidium bromide study, reducing both drugs from Ru^III to Ru^II resulted in a significant decrease in binding. Our findings suggest that the relatively large heteroaromatic indazole ligands of KP1019 intercalate in the π-stacks of tRNA^Phe within structurally complex binding pockets. In addition, NAMI-A appears to be sensitive to destabilizing electrostatic interactions with the negative phosphate backbone of tRNA^Phe. Interactions with additional tRNA molecules and other types of RNA require further evaluation to determine the role of RNA in the mechanisms of action for KP1019 and to better understand how Ru drugs fundamentally interact with biomolecules that are more structurally sophisticated than short DNA oligonucleotides. To the best of our knowledge, this is the first study to report KP1019 binding interactions with RNA.

Keywords: Anticancer drug; KP1019; Metallodrug; NAMI-A; RNA; Ruthenium; tRNA.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / chemistry*
Dimethyl Sulfoxide / analogs & derivatives*
Dimethyl Sulfoxide / chemistry
Indazoles / chemistry*
Organometallic Compounds / chemistry*
RNA / chemistry
RNA, Transfer, Phe / chemistry*
Ruthenium / chemistry*
Ruthenium Compounds

Substances

Antineoplastic Agents
Indazoles
Organometallic Compounds
RNA, Transfer, Phe
Ruthenium Compounds
imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III)
indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III))
RNA
Ruthenium
Dimethyl Sulfoxide