Routes to polysubstituted and condensed pyridines and diazines - utilization of 1,3-bielectrophiles and transition metal-based catalysis in ring synthesis/modification

The present work aimed to study the potential of well-known synthetic strategies for the synthesis of imidazo[4,5-b]pyridine-derived (or 1-desazapurine-derived), purine-derived and benzimidazole-derived moieties and their modifications. This includes [3+3] cyclocondensations, inverse electron-demand Diels-Alder reaction, intramolecular palladium-catalyzed arylation. In addition, unprecedented method of synthesis of 4-trifluoromethylpyridines was developed, including scope limitation and theoretical mechanistic studies with DFT methods.Die vorliegende Arbeit untersucht das Potential bekannter Synthesestrategien zum Aufbau von Derivaten des Imidazo[4,5-b]pyridins (1-Desazapurin), Purins und Benzimidazols. Dies beinhaltet [3+3] Zyklokondensationen, Inverse Diels-Alder Reaktionen sowie intramolekulare Palladium katalysierte Arylierungen. Außerdem wurde eine neue Methode für die Synthese von 4-Trifluoromethylpyridinen entwickelt, einschließlich der Eingrenzung der Anwendbarkeit und theoretischen mechanistischen Untersuchungen mittels DFT

Preparation data of the bromodomains BRD3(1), BRD3(2), BRD4(1), and BRPF1B and crystallization of BRD4(1)-inhibitor complexes

AbstractThis article presents detailed purification procedures for the bromodomains BRD3(1), BRD3(2), BRD4(1), and BRPF1B. In addition we provide crystallization protocols for apo BRD4(1) and BRD4(1) in complex with numerous inhibitors. The protocols described here were successfully applied to obtain affinity data by isothermal titration calorimetry (ITC) and by differential scanning fluorimetry (DSF) as well as structural characterizations of BRD4(1) inhibitor complexes (PDB codes: PDB: 4LYI, PDB: 4LZS, PDB: 4LYW, PDB: 4LZR, PDB: 4LYS, PDB: 5D24, PDB: 5D25, PDB: 5D26, PDB: 5D3H, PDB: 5D3J, PDB: 5D3L, PDB: 5D3N, PDB: 5D3P, PDB: 5D3R, PDB: 5D3S, PDB: 5D3T). These data have been reported previously and are discussed in more detail elsewhere [1,2]

4-Acyl Pyrrole Derivatives Yield Novel Vectors for Designing Inhibitors of the Acetyl-Lysine Recognition Site of BRD4(1)

Several human diseases, including cancer, show altered signaling pathways resulting from changes in the activity levels of epigenetic modulators. In the past few years, small-molecule inhibitors against specific modulators, including the bromodomain and extra-terminal (BET) bromodomain family of acetylation readers, have shown early promise in the treatment of the genetically defined midline carcinoma and hematopoietic malignancies. We have recently developed a novel potent inhibitor of BET proteins, <b>1</b> (XD14­[Angew. Chem., Int. Ed. 2013, 52, 14055]), which exerts a strong inhibitory potential on the proliferation of specific leukemia cell lines. In the study presented here, we designed analogues of <b>1</b> to study the potential of substitutions on the 4-acyl pyrrole backbone to occupy additional sites within the substrate recognition site of BRD4(1). The compounds were profiled using ITC, DSF, and X-ray crystallography. We could introduce several substitutions that address previously untargeted areas of the substrate recognition site. This work may substantially contribute to the development of therapeutics with increased target specificity against BRD4-related malignancies