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Cited by 296

The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.

Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2-Pyridyl-2-pyrimidine-4-carboxylic Acid

Pierroz, Vanessa, Joshi, Tanmaya, Leonidova, Anna, Mari, Cristina, Schur, Julia, Ott, Ingo, Spiccia, Leone, Ferrari, Stefano, Gasser, Gilles·2012·Journal of the American Chemical Society
DOI 10.1021/ja307288s
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Abstract

A great majority of the Ru complexes currently studied in anticancer research exert their antiproliferative activity, at least partially, through ligand exchange. In recent years, however, coordinatively saturated and substitutionally inert polypyridyl Ru(II) compounds have emerged as potential anticancer drug candidates. In this work, we present the synthesis and detailed characterization of two novel inert Ru(II) complexes, namely, [Ru(bipy)(2)(Cpp-NH-Hex-COOH)](2+) (2) and [Ru(dppz)(2)(CppH)](2+) (3) (bipy = 2,2'-bipyridine; CppH = 2-(2'-pyridyl)pyrimidine-4-carboxylic acid; Cpp-NH-Hex-COOH = 6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoic acid; dppz = dipyrido[3,2-a:2',3'-c]phenazine). 3 is of particular interest as it was found to have IC(50) values comparable to cisplatin, a benchmark standard in the field, on three cancer cell lines and a better activity on one cisplatin-resistant cell line than cisplatin itself. The mechanism of action of 3 was then investigated in detail and it could be demonstrated that, although 3 binds to calf-thymus DNA by intercalation, the biological effects that it induces did not involve a nuclear DNA related mode of action. On the contrary, confocal microscopy colocalization studies in HeLa cells showed that 3 specifically targeted mitochondria. This was further correlated by ruthenium quantification using High-resolution atomic absorption spectrometry. Furthermore, as determined by two independent assays, 3 induced apoptosis at a relatively late stage of treatment. The generation of reactive oxygen species could be excluded as the cause of the observed cytotoxicity. It was demonstrated that the mitochondrial membrane potential in HeLa was impaired by 3 as early as 2 h after its introduction and even more with increasing time.

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Metadata

Authors
Pierroz, V., Joshi, T., Leonidova, A., Mari, C., Schur, J., Ott, I., Spiccia, L., Ferrari, S., & Gasser, G.
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2012-12-11
Volume
134
Issue
50
Pages
20376-20387
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja307288s
OpenAlex
W2080503518
Cited by
296
References
54
FWCI
13.49
Type
journal article
Language
en
Open access
closed

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