Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.     

An alternative approach to nonlinear filtering

The structure of a nonlinear filter with observation process having continuous and discontinuous components is considered. The approach is based on the so-called “Bayes” formula for conditional expectations. “Fubini” type theorems for stochastic integrals are given and used to obtain the representations of an optimal estimate and of the conditional likelihood ratio. A linear unnormalized filtering equation for controlled system process is derived.     

α-Unsaturated 3-Amino-1-carboxymethyl-β-lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment

Innovative monocyclic β-lactam entities create opportunities in the battle against resistant bacteria because of their PBP acylation potential, intrinsically high β-lactamase stability and compact scaffold. α-Benzylidene-substituted 3-amino-1-carboxymethyl-β-lactams were recently shown to be potent PBP inhibitors and constitute eligible anchor points for synthetic elaboration of the chemical space around the central β-lactam ring. The present study discloses a 12-step synthesis of ten α-arylmethylidenecarboxylates using a microwave-assisted Wittig olefination as the crucial reaction step. The library was designed aiming at enhanced β-lactam electrophilicity and extended electron flow after enzymatic attack. Additionally, increased β-lactamase stability and intermolecular target interaction were envisioned by tackling both the substitution pattern of the aromatic ring and the β-lactam C4-position. The significance of α-unsaturation was validated and the R39/PBP3 inhibitory potency shown to be augmented the most through decoration of the aromatic ring with electron-withdrawing groups. Furthermore, ring cleavage by representative β-lactamases was ruled out, providing new insights in the SAR landscape of monocyclic β-lactams as eligible PBP or β-lactamase inhibitors.     

Synthesis and Penicillin‐binding Protein Inhibitory Assessment of Dipeptidic 4‐Phenyl‐β‐lactams from α‐Amino Acid‐derived Imines

Monocyclic β‐lactams revive the research field on antibiotics, which are threatened by the emergence of resistant bacteria. A six‐step synthetic route was developed, providing easy access to new 3‐amino‐1‐carboxymethyl‐4‐phenyl‐β‐lactams, of which the penicillin‐binding protein (PBP) inhibitory potency was demonstrated biochemically.     

Nonpeptidic Selective Inhibitors of the Chymotrypsin‐Like (β5 i) Subunit of the Immunoproteasome

Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide‐based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin‐like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell‐based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i‐selective probes for possible application in noncancer diseases related to the immunoproteasome.     

Synthesis and NMR spectroscopic assignment of chlorinated benzimidazole-2-thione derivatives

The benzimidazole-2-thione scaffold is present in many drugs encompassing various therapeutic areas. Due to the broad spectrum of bioactivities it also represents an important starting point in drug discovery campaigns, especially those based on fragment-based design. Despite simple structures the tautomerism and regioisomerism of substituted benzimidazole-2-thiones makes unambiguous structural analysis difficult. Tautomeric duplicates are present in commercial libraries resulting in two tautomers being sold as different products. To showcase an example of appropriate structural determination, we synthesized and characterized a set of benzimidazole-2-thiones with different positions of a chlorine atom on the ring. Using NOESY and ¹³C NMR spectroscopy, we determined that the thione tautomer predominates in the thione-thiol equilibrium. Furthermore, NOESY and HMBC experiments confirmed the position of the substituents on the benzimidazole-2-thione ring.     

Primary trifluoroborate-iminiums enable facile access to chiral α-aminoboronic acids via Ru-catalyzed asymmetric hydrogenation and simple hydrolysis of the trifluoroborate moiety

This work describes the first preparation and application of primary trifluoroborate-iminiums (pTIMs) as a new, easily accessible and valuable class of organoboron derivatives. An array of structurally diverse pTIMs was prepared from potassium acyltrifluoroborates in excellent yields. Highly efficient and enantioselective [(R,R)-TethTsDpen-RuCl] complex-catalyzed hydrogenation of pTIMs provided direct access to chiral primary trifluoroborate-ammoniums (pTAMs). Moreover, facile synthesis of a series of structurally diverse chiral α-aminoboronic acids from chiral pTAMs was accomplished through novel, operationally simple and efficient conversion using hexamethyldisiloxane/aqueous HCl. Using no chromatography at any point, this work allowed easy access to chiral α-aminoboronic acids, as exemplified by the synthesis of optically pure anti-cancer drugs bortezomib and ixazomib.

Starting with potassium acyltrifluoroborates (KATs), N-unprotected chiral α-aminoboronic acids are prepared in three simple steps without chromatography. This facile methodology will tap the broad potential of these valuable compounds.     

A microwave-assisted nucleophilic substitution reaction on a quinoline system: the synthesis of amino analogues of nitroxoline

A reliable protocol for the synthesis of a series of 8-amino analogues of pharmacologically interesting nitroxoline (5-nitro-8-hydroxyquinoline) is described. The unprecedented displacement of the cyanomethoxy group of an O-cyanomethylated quinoline derivative by various primary and secondary amines selectively affords 5-nitroquinolin-8-ylamines in moderate-to-high yields. The reactions were accelerated significantly under microwave conditions in comparison with conventional heating.