Adding Diversity to a Diruthenium Biscyclopentadienyl Scaffold via Alkyne Incorporation: Synthesis and Biological Studies.

We report the synthesis and the assessment of the anticancer potential of two series of diruthenium biscyclopentadienyl carbonyl complexes. Novel dimetallacyclopentenone compounds ( 2 - 4 ) were obtained (45-92% yields) from the thermal reaction (PhCCPh exchange) of [Ru 2 Cp 2 (CO)(μ-CO){μ-η 1 :η 3 -C(Ph)═C(Ph)C(═O)}], 1 , with alkynes HCCR [R = C 5 H 4 FeCp (Fc), 3-C 6 H 4 (Asp), 2-naphthyl; Cp = η 5 -C 5 H 5 , Asp = OC(O)-2-C 6 H 4 C(O)Me]. Protonation of 1 - 3 by HBF 4 afforded the corresponding μ-alkenyl derivatives 5 - 7 , in 40-86% yields. All products were characterized by IR and NMR spectroscopy; moreover, cyclic voltammetry ( 1 , 2 , 5 , 7 ) and single-crystal X-ray diffraction ( 5 , 7 ) analyses were performed on representative compounds. Complexes 5 - 7 revealed a cytotoxic activity comparable to that of cisplatin in A549 (lung adenocarcinoma), SW480 (colon adenocarcinoma), and ovarian (A2780) cancer cell lines, and 2 , 5 , 6 , and 7 overcame cisplatin resistance in A2780cis cells. Complexes 2 , 5 , and 7 (but not the aspirin derivative 6 ) induced an increase in intracellular ROS levels. Otherwise, 6 strongly stabilizes and elongates natural DNA (from calf thymus, CT-DNA), suggesting a possible intercalation binding mode, whereas 5 is less effective in binding CT-DNA, and 7 is ineffective. This trend is reversed concerning RNA, and in particular, 7 is able to bind poly(rA)poly(rU) showing selectivity for this nucleic acid. Complexes 5 - 7 can interact with the albumin protein with a thermodynamic signature dominated by hydrophobic interactions. Overall, we show that organometallic species based on the Ru 2 Cp 2 (CO) x scaffold ( x = 2, 3) are active against cancer cells, with different incorporated fragments influencing the interactions with nucleic acids and the production of ROS.