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Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Initiating encoded compound synthesis with solid phase -coupled DNA barcodes does benefi t from choice of organic solvents. Screening of more than 50 metal salts and organic reagents for DNA compatibility suggested reactions for encoded compound synthesis. A ZnCl2-mediated aza-Diels-Alder reaction with Danishefsky's diene and diphenyl phosphate-promoted tetrahydroquinoline and pyrimidinone syntheses by Povarov and Biginelli reactions, respectively, showed a broad substrate scope and were well tolerated by a DNA oligonucleotide.DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp 3 -bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl 2 -promoted aza-Diels-Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials. † Electronic supplementary information (ESI) available: Synthesis and additional tables for screening experiments, reaction optimization experiments and reaction scope. Copies of HPLC traces and MALDI-MS spectra are shown for all discussed DNA conjugates. See a For each: 20 nmol DNA, 200 equiv. (transition) metal salt or organocatalyst A-H, 50 mL dry solvent, r.t., 22 h. b 50 mL of the indicated aqueous acid. c 5 equiv. of metal salt were used. hexT 7 ¼ 5 0 -AcN-(CH 2 ) 6 -TTT TTT-3 0 -CPG, TC 8 ¼ 5 0 -TTC CTC TCC T-3 0 -CPG, ATC 9 ¼ 5 0 -TTA CTA CCT A-3 0 -CPG, ATGC 10 ¼ 5 0 -GTC ATG ATC T-3 0 -CPG, ACN ¼ acetonitrile, MeOH ¼ methanol. This journal is View Article Online c 1000 equiv. of amine 12 were used. d Yb(OTf) 3 was used instead of ZnCl 2 . e The 2 nd step of the reaction was performed overnight at 35 C. 10mer ATGC ¼ 5 0 -GTC ATG ATC T-3 0 , ACN ¼ acetonitrile. This journal isFig. 7 Cheminformatics analysis: A ¼ PCA plot of the DA-1(red), P (blue) and B (green) lib...

BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins by regulating their turnover via the two major protein degradation pathways, i.e. proteasomal degradation and macroautophagy. On the one hand, BAG3 competes with BAG1 for binding to HSP70, thereby preventing the proteasomal degradation of its client proteins. By functionally interacting with HSP70 and LC3, BAG3 also delivers polyubiquitinated proteins to the autophagy pathway. BAG3 exerts a number of key physiological functions, including an involvement in cellular stress responses, proteostasis, cell death regulation, development, and cytoskeletal dynamics. Conversely, aberrant BAG3 function/expression has pathophysiological relevance correlated to cardiomyopathies, neurodegeneration, and cancer. Evidence obtained in recent years underscores the fact that BAG3 drives several key hallmarks of cancer, including cell adhesion, metastasis, angiogenesis, enhanced autophagic activity, and apoptosis inhibition. This review provides a state-of-the-art overview on the role of BAG3 in stress and therapy resistance of cancer, with a particular focus on BAG3-dependent modulation of apoptotic signaling and autophagic/lysosomal activity.

Databases contain millions of reactions for compound synthesis, rendering selection of reactions for forward synthetic design of small molecule screening libraries, such as DNA-encoded libraries (DELs), a big data challenge....