Catalytic anticancer metallodrugs active at low doses could minimize side-effects, introduce novel mechanisms of action that combat resistance and widen the spectrum of anticancer-drug activity. Here we use highly stable chiral half-sandwich organometallic Os(II) arene sulfonyl diamine complexes, [Os(arene)(TsDPEN)] (TsDPEN, N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine), to achieve a highly enantioselective reduction of pyruvate, a key intermediate in metabolic pathways. Reduction is shown both in aqueous model systems and in human cancer cells, with non-toxic concentrations of sodium formate used as a hydride source. The catalytic mechanism generates selectivity towards ovarian cancer cells versus non-cancerous fibroblasts (both ovarian and lung), which are commonly used as models of healthy proliferating cells. The formate precursor N-formylmethionine was explored as an alternative to formate in PC3 prostate cancer cells, which are known to overexpress a deformylase enzyme. Transfer-hydrogenation catalysts that generate reductive stress in cancer cells offer a new approach to cancer therapy.

Antimicrobial polymers appear as a promising alternative to tackle the current development of bacterial resistance against conventional antibiotics as they rely on bacterial membrane disruption. This study investigates the effect of segmentation of hydrophobic and cationic functionalities on antimicrobial polymers over their selectivity between bacteria and mammalian cells. Using RAFT technology, statistical, diblock, and highly segmented multiblock copolymers were synthesized in a controlled manner. Polymers were analyzed by HPLC, and the segmentation was found to have a significant influence on their overall hydrophobicity. In addition, the amount of incorporated cationic comonomer was varied to yield a small library of bioactive macromolecules. The antimicrobial properties of these compounds were probed against pathogenic bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis), and their biocompatibility was tested using hemolysis and erythrocyte aggregation assays, as well as mammalian cell viability assays. In all cases, diblock and multiblock copolymers were found to outperform statistical copolymers, and for polymers with a low content of cationic comonomer, the multiblock showed a tremendously increased selectivity for P. aeruginosa and S. epidermidis compared to its statistical and diblock analogue. This work highlights the remarkable effect of segmentation on both the physical properties of the materials as well as their interaction with biological systems. Due to the outstanding selectivity of multiblock copolymers toward certain bacteria strains, the presented materials are a promising platform for the treatment of infections and a valuable tool to combat antimicrobial resistance.

Synthetic agents that bind to DNA and affect its processing are attractive targets in molecular design. Small molecules can regulate specific gene expression [1] and remain at the forefront of clinical application as anticancer and antiviral drugs.[2] Clinical drugs can intercalate (anthracycline antibiotics), [3] minor groove bind (berenil), [4] or form coordination bonds to DNA (cisplatin). [5] To create different spectra of activity and circumvent cross-resistance, it is important to explore drugs that interact with DNA in new and distinct ways.We have previously described synthetic metallo-supramolecular cylinders of a similar size and shape to protein zinc fingers. These tetracationic cylinders contain three bis(pyridylimine) ligand strands wrapped in a helical fashion about two iron(II) centers. The cylinders not only can bind strongly and noncovalently in the major groove of DNA, inducing dramatic and unprecedented intramolecular DNA coiling in natural polymeric DNAs, [2,6] but also can bind at the heart of Y-shaped DNA junctions, an unparalleled and hitherto unexpected mode of DNA recognition. [7] Combining these striking DNA binding features with the fact that ruthenium compounds represent a new and promising class of anticancer drugs [8][9][10] led to the aim of developing a triple-stranded ruthenium cylinder that would be one of the few noncovalent DNA recognition metal compounds studied for its biological activity. This design was still more attractive because of the potential for luminescence (from MLCT states), [11] which might be used to probe the DNA binding. We describe herein the synthesis of the luminescent ruthenium(II) triple-stranded helicate of ligand L (Scheme 1) and explore its DNA binding and activity against cancer cells.Although the synthesis of triple-stranded helicates with labile first-row transition metals is well established, [12] the synthesis of triple-stranded helicates with an inert metal such as ruthenium(II) represents a considerable challenge and prior to this work had not been achieved. Coordinate bond formation with labile metals is reversible and the assembly is under thermodynamic control. With inert metals this is not the case and the metals and ligands can become trapped in alternative polymeric structures that are not pathways to the assembly of the helicate; in illustration we note that of the three isomeric dinuclear double-stranded unsaturated ruthenium(II) helicates we recently described, none has the correct conformation at any of their metal centers needed for triple-helicate formation.[13] It is striking that, despite the great interest in the photophysical and redox properties of ruthenium(II) tris(diimine) centers, [14] no diruthenium(II) triple-stranded helicate has been prepared. [15] To try to prepare the triple-stranded diruthenium(II) complex, we initially explored different ruthenium starting materials ([{Ru(cod)Cl 2 } n ], RuCl 3 , and [Ru(CH 3 CN) 6 ](PF 6 ) 2 ; cod = 1,5-cyclooctodiene), which we heated under reflux with the ligand in a variety of o...

In eukaryotic cells, cargo is transported on self-organised networks of microtubule trackways by kinesin and dynein motor proteins1,2. Synthetic microtubule networks have previously been assembled in vitro3–5 and microtubules have been used as shuttles to carry cargoes on lithographically-defined tracks consisting of surface-bound kinesin motors6,7. Here we show that molecular signals can be used to program both the architecture and the operation of a self-organized transport system based on kinesin and microtubules and spans three orders of magnitude in length scale. A single motor protein - dimeric kinesin 18 - is conjugated to various DNA nanostructures to accomplish different tasks. Instructions encoded into the DNA sequences are used to direct the assembly of a polar array of microtubules and can be used to control the loading, active concentration and unloading of cargo on this track network or to trigger the disassembly of the network.