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ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl-acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.

Novel metallocene cryptand molecules have been synthesized exhibiting selective complexation of K + to the exclusion of either Li + , Na + or Cs + . This was demonstrated by fast atom bombardment mass spectrometry.

The condensation of 1,1′-bis(chlorocarbonyl)metallocenes and p-tert-butylcalix[4]arene in toluene leads to novel metallocene calix[4]arenes in which the metallocene subunit bridges the opposite hydroxy groups of the parent calixarene. © 1987 D. Reidel Publishing Company.

An autotrophic theory of the origin of metabolism and life has been proposed in which carbon dioxide is reduced by ferrous sulfide and hydrogen sulfide by means of a reversed citric acid cycle, leading to the production of amino acids. Similar processes have been proposed for purine synthesis. Ferrous sulfide is a strong reducing agent in the presence of hydrogen sulfide and can produce hydrogen as well as reduce alkenes, alkynes, and thiols to saturated hydrocarbons and reduce ketones to thiols. However, the reduction of carbon dioxide has not been demonstrated. We show here that no amino acids, purines, or pyrimidines are produced from carbon dioxide with the ferrous sulfide and hydrogen sulfide system. Furthermore, this system does not produce amino acids from carboxylic acids by reductive amination and carboxylation. Thus, the proposed autotrophic theory, using carbon dioxide, ferrous sulfide, and hydrogen sulfide, lacks the robustness needed to be a geological process and is, therefore, unlikely to have played a role in the origin of metabolism or the origin of life.

The syntheses of new ferrocene and ruthenocene bis(aza-crown ethers)(11)–(14) containing amide bond linkages between the metallocene redox centre and aza-15-crown-5 (1,4,7,10-tetraoxa-13-azacyclopentadecane) and aza-18-crown-6 (1,4,7,10,13-pentaoxa-16-azacyclo-octadecane) are described. Variable-temperature 13C n.m.r. studies on these compounds reveal a common intramolecular dynamic process involving rotation about the N–CO bond whose energy barrier to rotation is cation (Na+ or Li+) dependent. The sodium cation forms 1 : 2 stoicheiometric complexes with the ferrocene bis(aza-crown ethers), whereas potassium produces a 1 : 1 intramolecular sandwich complex with the former and a 1 : 2 complex with the latter. Electrochemical investigations reveal that binding of Na+ and K+ guest cations at the respective aza-crown ether co-ordinating sites results in shifts of the ferrocene oxidation wave to more positive potentials. Lithium produces analogous electrochemical effects with these two compounds, however 13C n.m.r. results suggest this cation exclusively co-ordinates to the respective amide carbonyl oxygen donor atoms. This rationalisation is supported by ‘model’ ferrocene bis(tertiary amide) derivatives which exhibit redox-responsive behaviour to Li+ while being electrochemically insensitive to Na+ and K+.

The syntheses and electrochemistry of four novel polycobalticinium macrocyclic receptor molecules are reported. Preliminary anion coordination studies in one case reveal the receptor to be redox responsive to the binding of a Br − guest anion, shifting the respective cobalticinium reduction wave to more negative potentials.

The condensation of ferrocene carbonylchloride (1) with p-t-butylcalix[4]arene (2) and calix[4]arene (3) leads to the respective novel redox-active hydrophobic host molecules containing two ferrocene moieties. An X-ray diffraction study of of one of the products shows that the calix[4]arene is in a cone conformation.