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

Abstract

High Resolution Image Download MS PowerPoint Slide 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.

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