Structure-Based Design of a Potent and Selective YTHDC1 Ligand.

N-Adenosine methylation (mA) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the cell nucleus. Here, we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor , which shows an equilibrium dissociation constant () of 49 nM. The crystal structure of the complex (1.

Proteolysis Targeting Chimera Degraders of the METTL3-14 mA-RNA Methyltransferase.

Methylation of adenine N6 (mA) is the most frequent RNA modification. On mRNA, it is catalyzed by the METTL3-14 heterodimer complex, which plays a key role in acute myeloid leukemia (AML) and other types of blood cancers and solid tumors. Here, we disclose the first proteolysis targeting chimeras (PROTACs) for an epitranscriptomics protein.

Fragment Ligands of the mA-RNA Reader YTHDF2.

We report 17 small-molecule ligands that compete with -methyladenosine (mA) for binding to the mA-reader domain of YTHDF2 (YT521-B homology domain family 2). We determined their binding mode at high resolution by X-ray crystallography and quantified their affinity by a fluorescence-based binding assay. 6-Cyclopropyluracil and a pyrazolopyrimidine derivative have favorable ligand efficiencies of 0.

Heteroaryl sulfonamide synthesis: scope and limitations.

Heteroaryl sulfonamides are important structural motifs in the medicinal and agrochemical industries. However, their synthesis often relies on the use of heteroaryl sulfonyl chlorides, which are unstable and toxic reagents. Herein, we report a protocol that allows direct oxidative coupling of heteroaryl thiols and primary amines, readily available and inexpensive commodity chemicals.

Unified Approach to Benzo[]thiazol-2-yl-Sulfonamides.

In this paper, we report a unified approach to -substituted and -disubstituted benzothiazole (BT) sulfonamides. Our approach to BT-sulfonamides starts from simple commercially available building blocks (benzo[]thiazole-2-thiol and primary and secondary amines) that are connected via (a) a S oxidation/S-N coupling approach, (b) a S-N coupling/S-oxidation sequence, or via (c) a S-oxidation/S-F bond formation/SuFEx approach. The labile N-H bond in -monoalkylated BT-sulfonamides (p (BTSON()Bn) = 3.

Trisubstituted Highly Activated Benzo[]thiazol-2-yl-sulfone-Containing Olefins as Building Blocks in Organic Synthesis.

In this paper, we report the formation of highly electrophilic 1,1-deactivated olefins, their use as novel synthetic building blocks, and their transformation to structurally diverse molecular scaffolds. Synthesis of 1,1-deactivated olefins substituted with a BT-sulfonyl group and a carbonyl or nitrile, respectively, consists of unusual Ti(OPr)-mediated Knoevenagel-type condensation and proceed in good to excellent yields. Generated olefins can be further transformed in a highly stereoselective manner and in good yields to various polyfunctionalized heterocycles and acyclic molecular scaffolds.

General Synthesis of 1-Aryl-6-azaisocytosines and Their Utilization for the Preparation of Related Condensed 1,2,4-Triazines.

A simple general synthesis of 1-aryl-6-azaisocytosine-5-carbonitriles is described. This method is based on coupling diazonium salts with cyanoacetylcyanamide and then cyclization of the formed 2-arylhydrazono-2-cyanoacetylcyanamides . The 6-azaisocytosines were studied with respect to tautomeric equilibrium and the transformation of functional groups, and used in the synthesis of the condensed heterocyclic compounds: Purine isosteric imidazo[2,1-]-[1,2,4]triazine and the 1,2,4-triazino[2,3-]quinazolines -.

Lignans and Neolignans: Plant secondary metabolites as a reservoir of biologically active substances.

Lignans and neolignans are plant secondary metabolites derived from the oxidative coupling of phenylpropanoids. Biological activity of these phenolic compounds ranges from antioxidant, antitumor (terminaloside P, IC = 10 nM), anti-inflammatory, anti-neurodegenerative (schibitubin B, IC = 3.2 nM) and antiviral (patentiflorin A, IC = 14-23 nM) to antimicrobial.

One and Two-Carbon Homologation of Primary and Secondary Alcohols to Corresponding Carboxylic Esters Using β-Carbonyl BT Sulfones as a Common Intermediate.

Herein we report the efficient one- and two-carbon homologation of 1° and 2° alcohols to their corresponding homologated esters via the Mitsunobu reaction using β-carbonyl benzothiazole (BT) sulfone intermediates. The one-carbon homologation approach uses standard Mitsunobu C-S bond formation, oxidation and subsequent alkylation, while the two-carbon homologation uses a less common C-C bond forming Mitsunobu reaction. In this latter case, the use of β-BT sulfone bearing esters lowers the p K sufficiently enough for the substrate to be used as a carbon-based nucleophile and deliver the homologated β-BT sulfone ester, and this superfluous sulfone group can then be cleaved.