Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study

Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase’s biology, with wide-reaching implications for drug development.     

Combating Multidrug‐Resistant Bacteria: Current Strategies for the Discovery of Novel Antibacterials

The introduction of effective antibacterial therapies for infectious diseases in the mid‐20th century completely revolutionized clinical practices and helped to facilitate the development of modern medicine. Many potentially life‐threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chemistry.     

Einige Beobachtungen über die Waschwirkung der Seifen

Ohne Zusammenfassung(Zweite Mitteilung.)(Institut für allgemeine Chemie.)Aus dem Französischen übersetzt von E. Mäkelt, Leipzig.(Eine dritte und vierte Mitteilung iolgen.)     

Visual spatial memory is enhanced in female rats (but inhibited in males) by dietary soy phytoestrogens

Background  

In learning and memory tasks, requiring visual spatial memory (VSM), males exhibit superior performance to females (a difference attributed to the hormonal influence of estrogen). This study examined the influence of phytoestrogens (estrogen-like plant compounds) on VSM, utilizing radial arm-maze methods to examine varying aspects of memory. Additionally, brain phytoestrogen, calbindin (CALB), and cyclooxygenase-2 (COX-2) levels were determined.     

Induction-driven stabilization of the anion-π interaction in electron-rich aromatics as the key to fluoride inclusion in imidazolium-cage receptors

Intermolecular interactions that involve aromatic rings are key processes in both chemical and biological recognition. It is common knowledge that the existence of anion-π interactions between anions and electron-deficient (π-acidic) aromatics indicates that electron-rich (π-basic) aromatics are expected to be repulsive to anions due to their electron-donating character. Here we report the first concrete theoretical and experimental evidence of the anion-π interaction between electron-rich alkylbenzene rings and a fluoride ion in CH(3)CN. The cyclophane cavity bridged with three naphthoimidazolium groups selectively complexes a fluoride ion by means of a combination of anion-π interactions and (C-H)(+)···F(-)-type ionic hydrogen bonds. (1)H NMR, (19)F NMR, and fluorescence spectra of 1 and 2 with fluoride ions are examined to show that only 2 can host a fluoride ion in the cavity between two alkylbenzene rings to form a sandwich complex. In addition, the cage compounds can serve as highly selective and ratiometric fluorescent sensors for a fluoride ion. With the addition of 1 equiv of F(-), a strongly increased fluorescence emission centered at 385 nm appears at the expense of the fluorescence emission of 2 centered at 474 nm. Finally, isothermal titration calorimetry (ITC) experiments were performed to obtain the binding constants of the compounds 1 and 2 with F(-) as well as Gibbs free energy. The 2-F(-) complex is more stable than the 1-F(-) complex by 1.87 kcal mol(-1), which is attributable to the stronger anion-π interaction between F(-) and triethylbenzene.