Modulation of the Meisenheimer complex metabolism of nitro-benzothiazinones by targeted C-6 substitution.

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered.

Bromo-substituted indirubins for inhibition of protein kinase-mediated signalling involved in inflammatory mediator release in human monocytes.

Targeting protein kinases that regulate signalling pathways in inflammation is an effective pharmacological approach to alleviate uncontrolled inflammatory diseases. In this context, the natural product indirubin and its 6-bromo-substituted analogue 6-bromoindirubin-3 -glycerol-oxime ether (6BIGOE; 1) were identified as potent inhibitors of glycogen synthase kinase-3β (GSK-3β). These inhibitors suppress the release of pro-inflammatory cytokines and prostaglandins (PG) from human monocytes.

Synthesis of β-Amino Acid Derivatives via Enantioselective Lewis Base Catalyzed N-Allylation of Halogenated Amides with Morita-Baylis-Hillman Carbonates.

Trifluoro- and trichloroacetamides serving as pronucleophiles undergo enantioselective Lewis base catalyzed N-allylation with Morita-Baylis-Hillman carbonates to produce enantioenriched β-amino acid derivatives. The reactions proceed as a kinetic resolution to give the allylation products and the remaining carbonates in good yields and high enantioselectivity. The obtained products are amenable to diastereoselective derivatization to produce a library of spiro-isoxazoline lactams.

Lewis-Base-Catalyzed -Allylation of Silyl Carbamate Latent Pronucleophiles with Allylic Fluorides.

Silyl carbamates, latent pronucleophile surrogates of carbamates, undergo allylation using allylic fluorides in the presence of common Lewis base catalysts. The reactions are rendered enantioselective in the presence of chiral Lewis base catalysts and produce suitably protected derivatives of enantioenriched chiral β-amino acids. The design of the latent pronucleophile featuring both a silyl group and an electron-deficient carbamate is instrumental in lowering the nucleophilicity of nitrogen and enabling enantioselective allylation in the presence of chiral cinchona alkaloid-based catalysts.

Biosynthetic incorporation of fluorinated amino acids into the nonribosomal peptide gramicidin S.

Fluorine is a key element in medicinal chemistry, as it can significantly enhance the pharmacological properties of drugs. In this study, we aimed to biosynthetically produce fluorinated analogues of the antimicrobial cyclic decapeptide gramicidin S (GS). However, our results show that the A-domain of the NRPS module GrsA rejects 4-fluorinated analogues of its native substrate Phe due to an interrupted T-shaped aromatic interaction in the binding pocket.

Natural products from reconstructed bacterial genomes of the Middle and Upper Paleolithic.

Major advances over the past decade in the field of ancient DNA are providing access to past paleogenomic diversity, but the diverse functions and biosynthetic capabilities of this growing paleome remain largely elusive. We investigated the dental calculus of 12 Neanderthals and 52 anatomically modern humans ranging from 100,000 years ago to the present and reconstructed 459 bacterial metagenome-assembled genomes. We identified a biosynthetic gene cluster shared by seven Middle and Upper Paleolithic individuals that allows for the heterologous production of a class of previously unknown metabolites that we name "paleofurans.

Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silyl Enol Ethers with Allylic Fluorides.

Lewis base catalyzed allylations of C-centered nucleophiles have been largely limited to the niche substrates with acidic C-H substituted for C-F bonds at the stabilized carbanionic carbon. Herein we report that the concept of latent pronucleophiles serves to overcome these limitations and allow for a variety of common stabilized C-nucleophiles, when they are introduced as the corresponding silylated compounds, to undergo enantioselective allylations using allylic fluorides. The reactions of silyl enol ethers afford the allylation products in good yields and with high degree of regio/stereoselectivity as well as diastereoselectivity when cyclic silyl enol ethers are used.

-Adenosylmethionine (SAM)-Dependent Methyltransferase MftM is Responsible for Methylation of the Redox Cofactor Mycofactocin.

Mycobacteria produce several unusual cofactors that contribute to their metabolic versatility and capability to survive in different environments. Mycofactocin (MFT) is a redox cofactor involved in ethanol metabolism. The redox-active core moiety of mycofactocin is derived from the short precursor peptide MftA, which is modified by several maturases.

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function.

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure.

Selective C-H chalcogenation of thiazoles via thiazol-2-yl-phosphonium salts.

Thiazoles and benzothiazoles undergo regioselective C2-H chalcogenation via the sequence of thiazole C2-functionalization with phosphines to produce phosphonium salts which in turn react with S- and Se-centered nucleophiles to give products of C2-H chalcogenation and allow for recovery of the starting phosphine. The atom economical sequence proceeds under mild conditions and features broad scope for both the nucleophiles (electron-rich, electron-poor, sterically hindered thiols) and the various substituted benzothiazoles. The access to the substituted medicinally relevant C2-thio benzothiazoles also enables stereoselectivity improvements in the modified Julia olefinations.

Enantioselective Lewis base catalyzed phosphonyldifluoromethylation of allylic fluorides using a C-silyl latent pronucleophile.

The first enantioselective phosphonyldifluoromethylation is enabled by the use of diethyl (difluoro(trimethylsilyl)-methyl)phosphonate reagent as a latent pronucleophile in the Lewis base catalyzed substitution of allylic fluorides. The reaction proceeds as a kinetic resolution to produce both the difluoromethylphosphonate products and the remaining fluorides in good yields and with high stereoselectivity. The use of cinchona based alkaloid catalysts enables the facile synthesis of both enantiomers of the difluoromethylphosphonate products.

C-H Functionalization of Benzothiazoles via Thiazol-2-yl-phosphonium Intermediates.

Benzothiazoles undergo regioselective C2-H functionalization with triphenylphosphine to form thiazol-2-yl-triphenylphosphonium salts, and these phosphonium salts react with a wide range of O- and N-centered nucleophiles to give the corresponding ethers, amines, and C-N biaryls. The reactions proceed under mild conditions and allow for the recovery of triphenylphosphine at the end of the sequence. In the presence of hydroxide, phosphonium salts undergo disproportionation, resulting in the reduction of the benzothiazole, which is useful for specific C2 deuteration of benzothiazoles.

Robust synthesis of NIR-emissive P-rhodamine fluorophores.

P-Rhodamines were accessed by implementing a robust three step sequence consisting of (i) addition of m-metallated anilines to dichlorophosphine oxides, (ii) selective dibromination, and (iii) cyclization of the diaryllithium reagents derived from the dibromides to form the dihydroacridophosphine core of P-rhodamines. A modified route was developed to produce non-symmetric P-rhodamines. A library of prepared P-rhodamines provides first insight into dependence of fluorophore properties on the structure of P-rhodamines.

Synthesis of Allylboranes via Cu(I)-Catalyzed B-H Insertion of Vinyldiazoacetates into Phosphine-Borane Adducts.

Cu(I) catalysts enable C-B bond formation via direct insertion of vinyldiazoacetates into B-H bonds of borane-phosphine Lewis adducts to form phosphine-protected allylboranes under mild conditions. The resulting allylborane-phosphine Lewis adducts can be used in the diastereoselective allylation of aldehydes directly without the need for removal of the phosphine. The allylation reaction proceeds with high diastereoselectivity and yields 5,6-disubstituted dihydropyranones after treatment with an appropriate acid.

Enantioselective Synthesis of Pyrrolizin-1-ones via Lewis Base Catalyzed N-Allylation of -Silyl Pyrrole Latent Nucleophiles.

Pyrrolizidine alkaloids and their derivatives often feature interesting biological activities. A class of substituted 2,3-dihydro-1-pyrrolizin-1-one derivatives has been explored as a potential treatment for Alzheimer's disease, but enantioselective synthesis of these molecules is still elusive. We report that enantioselective N-allylation of -silyl pyrrole latent nucleophiles with allylic fluorides followed by hydrogenation and diastereoselective Friedel-Crafts cyclization constitute an efficient synthetic route to access enantioenriched substituted 2,3-dihydro-1-pyrrolizin-1-ones.

Latent Nucleophiles in Lewis Base Catalyzed Enantioselective N-Allylations of N-Heterocycles.

Latent nucleophiles are compounds that are themselves not nucleophilic but can produce a strong nucleophile when activated. Such nucleophiles can expand the scope of Lewis base catalyzed reactions. As a proof of concept, we report that N-silyl pyrroles, indoles, and carbazoles serve as latent N-centered nucleophiles in substitution reactions of allylic fluorides catalyzed by Lewis bases.

trans-Hydroboration vs. 1,2-reduction: divergent reactivity of ynones and ynoates in Lewis-base-catalyzed reactions with pinacolborane.

Ynones and ynoates react with pinacolborane in a divergent manner in the presence of nucleophilic phosphine catalysts. Ynones are transformed to the corresponding propargyl alcohols in good yields with high regio- and chemoselectivity. Ynoates undergo highly regio- and stereoselective trans-hydroboration to produce E-vinylboronates.

Surface enhanced Raman spectroscopy-detection of the uptake of mannose-modified nanoparticles by macrophages in vitro: A model for detection of vulnerable atherosclerotic plaques.

Atherosclerosis is a process of thickening and stiffening of the arterial walls through the accumulation of lipids and fibrotic material, as a consequence of aging and unhealthy life style. However, not all arterial plaques lead to complications, which can lead to life-threatening events such as stroke and myocardial infarction. Diagnosis of the disease in early stages and identification of unstable atherosclerotic plaques are still challenging.

Lewis-base-catalysed selective reductions of ynones with a mild hydride donor.

Ynones are efficiently reduced with a mild hydride donor in the presence of a catalytic amount of nucleophilic phosphines. The reactions are selective 1,2-reductions that give propargyl alcohols in yields of up to 96%. It is proposed that success in these reactions depends on the activation of ynones by a Lewis base catalyst.

Synthesis of Galactosylated Glycosylphosphatidylinositol Derivatives from Trypanosoma brucei.

Trypanosoma brucei uses variant surface glycoproteins (VSGs) to evade the host immune system and ensure parasitic longevity in animals and humans. VSGs are attached to the cell membrane by complex glycosylphosphatidylinositol anchors (GPI). Distinguishing structural feature of VSG GPIs are multiple α- and β-galactosides attached to the conserved GPI core structure.

Versatility of a glycosylphosphatidylinositol fragment in forming highly ordered polymorphs.

Glycosylphosphatidylinositols (GPIs) are often attributed with the ability to associate with the organized membrane microdomains. GPI fragment 1 forms a highly ordered subgel-phase structure characterized by ordering of both headgroups and alkyl chains in thin layers. While investigating the driving forces behind the formation of these ordered monolayers, we have studied polymorphism of 1 under different conditions employing surface-sensitive X-ray diffraction methods.

A comparative structural study in monolayers of GPI fragments and their binary mixtures.

Glycosylphosphatidylinositols (GPIs), natural complex glycolipids essential for a range of biological functions, are poorly understood with regard to their interactions and arrangements in cellular membranes. To evaluate the role of the head group in the structure formation in 2D model membranes (monolayers formed at the soft air/liquid interface), we employed the highly surface sensitive grazing incidence X-ray diffraction technique to investigate three GPI-fragments bearing the same hydrophobic part but different head groups. Condensed monolayers of simple GPI fragments are defined only by ordered alkyl chains.