Synthesis, Characterization, and in Vitro Evaluation of a Potentially Selective Anticancer, Mixed-Metal [Ruthenium(III)−Platinum(II)] Trinuclear Complex

Abstract

A new type of mixed-metal trinuclear complex containing platinum(II) and ruthenium(III) fragments that resemble both cisplatin and NAMI-A has been synthesized and characterized by IR, 1H NMR, elemental analysis, and X-ray crystallography. The water-soluble compound Na2{trans,cis,trans-[RuIIICl4(DMSO-S)(mu-pyz)]2PtIICl2} (AH-197, pyz = pyrazine) was assessed for its effects on DNA mobility and toxicity against human cancer cell lines. When compared to cisplatin and KP-1019 (which structurally resembles NAMI-A), IC50 results showed that AH-197 had an intermediate toxicity. When this data was coupled with a subsequent COMPARE evaluation (standard COMPARE queries resulted in insignificant correlation coefficients (<0.70) while very low COMPARE correlation coefficients were found in the matrix queries as well), AH-197 yielded a correlation coefficient of 0.19 when compared to cisplatin and 0.25 when compared to KP1019 indicating that AH-197 has a unique behavior.

Heterometallic Multinuclear Complexes as Anti‐Cancer Agents‐An Overview of Recent Developments

“…Three approaches have become apparent in the combination of platinum and ruthenium; 1) the development of complexes containing cisplatin and NAMI‐A fragments, 2) the combination of ruthenium‐arene complexes (which have shown promising in‐vitro anti‐cancer activity) with platinum fragments and 3) the incorporation of luminescent ruthenium fragments into platinum‐containing complexes to facilitate its use as a diagnostic agent or application in photodynamic therapy. Anderson and colleagues followed the first strategy and reported a trinuclear mixed‐metal complex which incorporated two Ru III centres and one Pt II centre, AH‐197 (Figure ). This water‐soluble complex displayed significant cytotoxicity against leukemia and two colon cancer cell lines, with IC 50 values comparable to that of cisplatin under the same conditions.…”

“…This water‐soluble complex displayed significant cytotoxicity against leukemia and two colon cancer cell lines, with IC 50 values comparable to that of cisplatin under the same conditions. DNA binding studies revealed that the compound interacts with DNA and that the presence of the two Ru‐centres enhances the interaction when compared to cisplatin on its own . Further investigation by the same group revealed that the inclusion of two ruthenium centres in the complex also improved the anti‐metastatic properties of the compound when compared to a hetero‐binuclear analogue, IT127 .…”

“…The Pt II ‐Ru III complexes, IT127 and AH‐197 , and the macrocyclic rectangles investigated by Chi and colleagues . The IC 50 (µM) values reported are shown below the chemical structures.…”

Development of ruthenium-based complexes as anticancer agents: toward a rational design of alternative receptor targets

“…NAMI-A and RAPTA-T seem to be highly effective against metastases, whereas KP1019 showed good activity toward primary tumors. Apart from these compounds, other Ru-based complexes have been synthesized and their potentials as anticancer agents have been evaluated (Grguric-Sipka et al 2003, Hotze et al 2003, Wu et al 2003, 2009, Cabrera et al 2004, Mazumder et al 2004, Brindell et al 2005, Jakupec et al 2005, Waern et al 2005, Deubel and Lau 2006, Romerosa et al 2006, Karki et al 2007, Pascu et al 2007, Schmid et al 2007, Singh et al 2007, Giovagnini et al 2008, Herman et al 2008, Kowol et al 2008, Rajendiran et al 2008, Vrábel et al 2008, Camm et al 2009, Corral et al 2009, Helena et al 2009, Kandioller et al 2009, Mendoza-Ferri et al 2009, Fetzer et al 2011, Kamatchi et al 2012, Loughrey et al 2012. At present, NAMI-A-and RAPTA-based compounds are still the best alternatives for further derivatization.…”

Crystallographic studies of chromatin-targeting metal-based compounds and nucleosome core particles assembled with engineerd cohesive end DNA fragments

“…Previous efforts with hetero-dinuclear platinum-ruthenium compounds focused on a ruthenium(III)-platinum(II) complex (Herman A. et al, 2008), a complex with reversible or irreversible oxidation states (Ru II ⇌ Ru III , Pt II → Pt IV ; Higgins S.L. et al, 2011), or a ruthenium(II)-platinum(II) compound (Houten, B.V. et al, 1993;Prussin, A.J.…”