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Aurora kinases and protein kinase C (PKC) have been shown to be involved in different aspects of cancer progression. To date, no dual Aurora/PKC inhibitor with clinical efficacy and low toxicity is available. Here, we report the identification of compound 2e as a potent small molecule capable of selectively inhibiting Aurora A kinase and PKC isoforms α, β1, β2 and θ. Compound 2e demonstrated significant inhibition of the colony forming ability of metastatic breast cancer cells in vitro and metastasis development in vivo . In vitro kinase screening and molecular modeling studies revealed the critical role of the selenium-containing side chains within 2e , where selenium atoms were shown to significantly improve its selectivity and potency by forming additional interactions and modulating the protein dynamics. In comparison to other H-bonding heteroatoms such as sulfur, our studies suggested that these selenium atoms also confer more favorable PK properties.

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CL pro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CL pro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CL pro . We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The long-standing history of platinum coordination complexes in nucleic acid recognition attests to the unique suitability of such species for therapeutic applications. Here, we report the synthetic exploration and development of a family of di-imine ligands, and their platinum(II) complexes, elaborated on a 3-(2-pyridyl)-[1,2,4]triazolo[4,3-a]pyridine platform which, in its unsubstituted form, has recently been shown to display exceptional capabilities for guanine quadruplex (G4) targeting. The identification of facile, high-yielding synthetic methods for the derivatization of this platform for the incorporation of additional sites of interactions with guanine quadruplex loops and grooves, along with the optimization of platinum(II) complexation methods, are discussed. Gratifyingly, preliminary biophysical screening of this novel family of binders validates all but one family members as robust G4 binders and highlights enhanced selectivity for quadruplex versus duplex DNA compared to the parent compound. These results bear promise for practical developments based on this platform., (© 2021 Wiley-VCH GmbH.)

The MYC oncogene is considered to be a high priority target for clinical intervention in cancer patients due to its aberrant activation in more than 50% of human cancers. Direct small molecule inhibition of MYC has traditionally been hampered by its intrinsically disordered nature and lack of both binding site and enzymatic activity. In recent years, however, a number of strategies for indirectly targeting MYC have emerged, guided by the advent of protein structural information and the growing set of computational tools that can be used to accelerate the hit to lead process in medicinal chemistry. In this review, we provide an overview of small molecules developed for clinical applications of these strategies, which include stabilization of the MYC guanine quadruplex, inhibition of BET factor BRD4, and disruption of the MYC:MAX heterodimer. The recent identification of novel targets for indirect MYC inhibition at the protein level is also discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Guanine quadruplex recognition has gained increasing attention, inspired by the growing awareness of the key roles played by these non-canonical nucleic acid architectures in cellular regulatory processes. We report here the solution and solid-state studies of a novel planar platinum(II) complex that is easily assembled from a simple ligand, and exhibits notable binding affinity for guanine quadruplex structures, while maintaining good selectivity for guanine quadruplex over duplex structures. A crystal structure of this ligand complexed with a telomeric quadruplex confirms double end-capping, with dimerization at the 5' interface., (© 2020 Wiley-VCH GmbH.)

The 2-(1,2,3-triazol-4-yl)pyridine motif, with its facile "click" synthesis and remarkable coordinative properties, is an attractive chelate for applications in the metal-directed self-assembly of intricate three-dimensional structures. Organic ligands that bear two such chelates bridged by flexible hinge moieties readily undergo self-assembly with metal ions of different coordination geometries to generate a series of topologically diverse metallomacrocycles that can be used for numerous applications. Herein, the synthesis and self-assembly of one such ligand with zinc(II), copper(II), and palladium(II) ions is reported, and the stability of the resulting metallomacrocycles described. An investigation into the use of these metallomacrocycles for the recognition of both small-molecule substrates, such as deoxyguanosine monophosphate, and larger biological assemblies, such as DNA and RNA guanine quadruplexes, is also described., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Coordination-driven self-assembly has been established as an effective strategy for the efficient construction of intricate architectures in both natural and artificial systems, for applications ranging from gene regulation to metal-organic frameworks. Central to these systems is the need for carefully designed organic ligands, generally with rigid components, that can undergo self-assembly with metal ions in a predictable manner. Herein, we report the synthesis and study of three novel organic ligands that feature 3,6-disubstituted acridine as a rigid spacer connected to two 2-(1,2,3-triazol-4-yl)pyridine "click" chelates through hinges of the same length but differing flexibility. The flexibility of these "three-atom" hinges was modulated by i) moving from secondary to tertiary amide functional groups and ii) replacing an sp 2 amide carbon with an sp 3 methylene carbon. In an effort to understand the role of hinge flexibility in directing self-assembly into mononuclear loops or dinuclear cylinders, the impact of these changes on self-assembly outcomes with zinc(II), iron(II), and copper(II) ions is described., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

At the cellular level, numerous processes ranging from protein folding to disease development are mediated by a sugar-based molecular information system that is much less well known than its DNA- or protein-based counterparts. The subtle structural diversity of such sugar tags nevertheless offers an excellent, if challenging, opportunity to design receptors for the selective recognition of biorelevant sugars. Over the past 40 years, growing interest in the field of sugar recognition has led to the development of several promising artificial receptors, which could soon find widespread use in medical diagnostics and cell imaging., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)