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Anticancer Activity of Hydrogen‐Bond‐Stabilized Half‐Sandwich Ru II Complexes with Heterocycles
Author(s) -
Mitra Raja,
Das Sangeeta,
Shinde Sridevi V.,
Sinha Sarika,
Somasundaram Kumaravel,
Samuelson Ashoka G.
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200938
Subject(s) - ruthenium , ligand (biochemistry) , hydrogen bond , chemistry , stereochemistry , cytotoxicity , dna , ring (chemistry) , metal , crystallography , molecule , in vitro , catalysis , organic chemistry , receptor , biochemistry
Neutral half‐sandwich organometallic ruthenium(II) complexes of the type [(η 6 ‐cymene)RuCl 2 (L)] ( H1 – H10 ), where L represents a heterocyclic ligand, have been synthesized and characterized spectroscopically. The structures of five complexes were also established by single‐crystal X‐ray diffraction confirming a piano‐stool geometry with η 6 coordination of the arene ligand. Hydrogen bonding between the NH group of the heterocycle and a chlorine atom attached to Ru stabilizes the metal–ligand interaction. Complexes coordinated to a mercaptobenzothiazole framework ( H1 ) or mercaptobenzoxazole ( H6 ) showed high cytotoxicity against several cancer cells but not against normal cells. In vitro studies have shown that the inhibition of cancer cell growth involves primarily G1‐phase arrest as well as the generation of reactive oxygen species (ROS). The complexes are found to bind DNA in a non‐intercalative fashion and cause unwinding of plasmid DNA in a cell‐free medium. Surprisingly, the cytotoxic complexes H1 and H6 differ in their interaction with DNA, as observed by biophysical studies, they either cause a biphasic melting of the DNA or the inhibition of topoisomerase IIα activity, respectively. Substitution of the aromatic ring of the heterocycle or adding a second hydrogen‐bond donor on the heterocycle reduces the cytotoxicity.