3586-12-7Relevant articles and documents
Catalytic production of anilines by nitro-compounds hydrogenation over highly recyclable platinum nanoparticles supported on halloysite nanotubes
Aepuru, Radhamanohar,Bustamante, Tatiana M.,Campos, Cristian H.,Leal-Villarroel, Edgardo,Mangalaraja, Ramalinga Viswanathan,Shanmugaraj, Krishnamoorthy,Torres, Cecilia C.,Vinoth, Victor
, (2021/07/28)
Pt-nanoparticles supported on halloysite-nanotubes (HNTs) were selectively deposited onto the inner (Pt(IN)/HNT) or outer (Pt(OUT)/HNT) surface of the support to evaluate their operational stability on the cleaner and efficient hydrogenation of nitro compounds to produce their corresponding anilines. The formation of Pt0-aggregates on the inner or outer surfaces was observed, with mean particles sizes of 2.4–2.9 nm. The catalysts were evaluated using ethanol as solvent and nitrobenzene as a model substrate at a temperature of 298 K, under 1 bar of H2 pressure. The Pt(IN)/HNT catalyst showed better catalytic performance than Pt(OUT)/HNT, which was mainly attributed to the confinement effect of the Pt-nanoparticles inside the HNTs. However, the operational stability showed that Pt(OUT)/HNT retained its catalytic performance after 15 cycles, while the Pt(IN)/HNT catalyst suffered deactivation after the 5th cycle. The best catalytic system showed a moderate-to-high efficiency in the efficient hydrogenation of 7 nitro compounds used to produce their corresponding anilines, which are important pharmaceutical building blocks.
Discovery of PqsE Thioesterase Inhibitors for Pseudomonas aeruginosa Using DNA-Encoded Small Molecule Library Screening
Bassler, Bonnie L.,Carson, Kenneth G.,Henke, Brad R.,Hone, Graham A. B.,Smith, Chari D.,Stergioula, Vasiliki,Taylor, Isabelle R.,Tota, Michael R.,Valastyan, Julie S.
, (2020/01/31)
Pseudomonas aeruginosa is a leading cause of hospital-acquired infections in the United States. PqsE, a thioesterase enzyme, is vital for virulence of P. aeruginosa, making PqsE an attractive target for inhibition. Neither the substrate nor the product of PqsE catalysis has been identified. A library of 550 million DNA-encoded drug-like small molecules was screened for those that bind to the purified PqsE protein. The structures of the bound molecules were identified by high throughput sequencing of the attached DNA barcodes. Putative PqsE binders with the strongest affinity features were examined for inhibition of PqsE thioesterase activity in vitro. The most potent inhibitors were resynthesized off DNA and examined for the ability to alter PqsE thermal melting and for PqsE thioesterase inhibition. Here, we report the synthesis, biological activity, mechanism of action, and early structure-activity relationships of a series of 2-(phenylcarbamoyl)benzoic acids that noncompetitively inhibit PqsE. A small set of analogs designed to probe initial structure-activity relationships showed increases in potency relative to the original hits, the best of which has an IC50 = 5 μM. Compound refinement is required to assess their in vivo activities as the current compounds do not accumulate in the P. aeruginosa cytosol. Our strategy validates DNA-encoded compound library screening as a rapid and effective method to identify catalytic inhibitors of the PqsE protein, and more generally, for discovering binders to bacterial proteins revealed by genetic screening to have crucial in vivo activities but whose biological functions have not been well-defined.
Cell-Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit
Stubba, Daniel,Bensinger, Dennis,Steinbacher, Janika,Proskurjakov, Lilia,Salcedo Gómez, álvaro,Schmidt, Uwe,Roth, Stefan,Schmitz, Katja,Schmidt, Boris
, p. 2005 - 2022 (2019/11/22)
The ubiquitin-proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly-reversibly binding boronates, optimization of novel covalent-reversibly binding warheads remains largely unattended. We previously reported α-ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy-substituted α-ketoamides combining the structure-activity relationships from the primed and the non-primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3-phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time-dependent inhibition of cellular substrate conversion. Furthermore, the α-ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity.