Organometallics, such as copper compounds, are cancer chemotherapeutics used alone or in combination with other drugs. One small group of copper complexes exerts an effective inhibitory action on topoisomerases, which participate in the regulation of DNA topology. Copper complexes inhibitors of topoisomerases 1 and 2 work by different molecular mechanisms, analyzed herein. They allow genesis of DNA breaks after the formation of a ternary complex, or act in a catalytic mode, often display DNA intercalative properties and ROS production, and sometimes display dual effects. These amplified actions have repercussions on the cell cycle checkpoints and death effectors. Copper complexes of topoisomerase inhibitors are analyzed in a broader synthetic view and in the context of cancer cell mutations. Finally, new emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.

Four novel biobased monomers (i.e. two diesters and two hydroxyesters) bearing a tertiary amine in their backbone have been synthesized from the sustainable methyl levulinate and amino-alcohols/amino-esters derived from natural amino acids. Their homopolymerization/copolymerization with diols leads to six poly(amine-co-ester)s with various microstructures. These families of biodegradable polyesters have been reported to be efficient carriers for gene delivery. The polymers are carefully characterized by nuclear magnetic resonance spectroscopy (¹H and ¹³C NMR) and size exclusion chromatography (SEC), and exhibit molecular weights (M_n) up to 36 kg mol⁻¹ and dispersities (Đ) between 1.5 and 2.1. They also present good solubility in aqueous acidic media due to amine protonation. Such properties are promising for applications in the biomedical field or in personal care products.

Topoisomerases are interesting targets in cancer chemotherapy. Here, we describe the design and synthesis of a novel copper(II) indenoisoquinoline complex, WN198. The new organometallic compound exhibits a cytotoxic effect on five adenocarcinoma cell lines (MCF-7, MDA-MB-231, HeLa, HT-29, and DU-145) with the lowest IC₅₀ (0.37 ± 0.04 μM) for the triple-negative MDA-MB-231 breast cancer cell line. Below 5 µM, WN198 was ineffective on non-tumorigenic epithelial breast MCF-10A cells and Xenopus oocyte G2/M transition or embryonic development. Moreover, cancer cell lines showed autophagy markers including Beclin-1 accumulation and LC3-II formation. The DNA interaction of this new compound was evaluated and the dose-dependent topoisomerase I activity starting at 1 μM was confirmed using in vitro tests and has intercalation properties into DNA shown by melting curves and fluorescence measurements. Molecular modeling showed that the main interaction occurs with the aromatic ring but copper stabilizes the molecule before binding and so can putatively increase the potency as well. In this way, copper-derived indenoisoquinoline topoisomerase I inhibitor WN198 is a promising antitumorigenic agent for the development of future DNA-damaging treatments.