Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis.

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.

Stereoselective Synthesis of Allylic Alcohols via Substrate Control on Asymmetric Lithiation.

Allylic alcohols are a privileged motif in natural product synthesis and new methods that access them in a stereoselective fashion are highly sought after. Toward this goal, we found that chiral acetonide-protected polyketide fragments performing the Hoppe-Matteson-Aggarwal rearrangement in the absence of sparteine with high yields and diastereoselectivities rendering this protocol a highly valuable alternative to the Nozaki-Hiyama-Takai-Kishi reaction. Various stereodyads and -triads were investigated to determine their substrate induction. The mostly strong inherent stereoinduction was attributed to a combination of steric and electronic effects.

Development of the Synthesis of Desepoxy-Tedanolide C.

We are presenting the development of our route for the total synthesis of desepoxy-tedanolide C. Through the obtained analytical data, the proposed structure of tedanolide C is questioned and a different configuration for this natural product is proposed. Key steps of the synthesis are a Kiyooka aldol reaction that builds up the tertiary alcohol flanked by three oxygenated carbon atoms and two aldol reactions used for fragment couplings. A Julia-Kocienski olefination was used for installation of the side chain. Besides the successful synthesis, the development for the protecting group setup of the southwestern hemisphere is described in detail as well as another retrosynthetic attempt for building up the target molecule.

Asymmetric Total Synthesis of Illisimonin A.

The discovery of illisimonin A in 2017 extended the structural repertoire of the Illicium sesquiterpenoids─a class of natural products known for their high oxidation levels and neurotrophic properties─with a new carbon backbone combining the strained trans-pentalene and norbornane substructures. We report an asymmetric total synthesis of (-)-illisimonin A that traces its tricyclic carbon framework back to a spirocyclic precursor, generated by a tandem-Nazarov/ene cyclization. As crucial link between the spirocyclic key intermediate and illisimonin A, a novel approach for the synthesis of tricyclo[5.2.1.01,5]decanes via radical cyclization was explored. This approach was applied in a two-stage strategy consisting of Ti(III)-mediated cyclization and semipinacol rearrangement to access the natural product's carbon backbone. These key steps were combined with carefully orchestrated C-H oxidations to establish the dense oxidation pattern.

1,2-Metallate Rearrangement as a Toolbox for the Synthesis of Allylic Alcohols.

The development of new methods and protocols for the synthesis of biologically active substances remains one of the most important pillars in organic chemistry, and one of these privileged structural motifs are allylic alcohols. The method of choice to date for the synthesis of these is the Nozaki-Hiyama-Takai-Kishi reaction. We describe here a valuable alternative to the synthesis of allylic alcohols via 1,2-metallate rearrangement. In this work, various vinyl boronic esters with different functional groups have been applied in the Hoppe-Matteson-Aggarwal reaction. In addition, two monoterpenoids were constructed via this convergent synthetic strategy.

Synthesis of Desepoxy-Tedanolide C.

The synthesis of desepoxy-tedanolide C was accomplished and provided experimental evidence on the configuration of tedanolide C. The reported chemical shifts and coupling constants point to a configuration different from the published structure and analogous to the structures of the other members of this family of natural products. The key step is a Kiyooka aldol protocol for the stereoselective synthesis of the tertiary alcohol flanked by three additional oxygenated carbon atoms. Furthermore, two additional aldol reactions and a Julia-Kocienski olefination were used to assemble the carbon framework.

Total Synthesis and Structure Revision of Halioxepine.

The first total synthesis of halioxepine is accomplished using a 1,4-addition for constructing the quaternary center at C10 and a halo etherification for the generation of the tertiary ether at C7. The correct structure of halioxepine was determined by assembling different enantiomeric building blocks and by changing the relative configuration between C10 and C15.

A Nazarov-Ene Tandem Reaction for the Stereoselective Construction of Spiro Compounds.

The different reactivity of trienones under Lewis and Brønsted acids catalysis was investigated, resulting in distinct cyclization products and carbon backbones that originated either from a conjugate Prins cyclization or an interrupted Nazarov cyclization. In particular, an unprecedented Nazarov cyclization tandem reaction is presented, terminating the oxyallyl cation by an ene-type reaction, and leading stereoselectively to bicyclic spiro compounds. The terminal olefin of this motif represents a useful handle for further functionalization, making it a strategic intermediate in total syntheses. The tandem Nazarov/ene cyclization was shown to be preferred over a Nazarov/[3+2] tandem reaction for all our substrates, independent of chain length. Deuteration studies further support the mechanistic hypothesis of the terminating ene reaction.

Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain-A new treatment strategy for neonatal seizures?

OBJECTIVES: The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ-aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N-dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB. METHODS: In the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats. RESULTS: Serum from 1- to 2-day-old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide. SIGNIFICANCE: These data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add-on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures.

Hydrazine clubbed 1,3-thiazoles as potent urease inhibitors: design, synthesis and molecular docking studies.

Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles (5a-m) has been described by reacting hydrazine-1-carbothioamides (3a-k) with α-chloro- or bromo-acetophenones (4a-d) in refluxing ethanol in good to excellent yields (65-86%). Structural confirmation was based upon spectroscopic techniques such as 1H-NMR, 13C-NMR, FT-IR and mass spectrometry. The biological application of these motifs has been demonstrated in terms of their strong urease inhibition activity. The results of in vitro study revealed that all the compounds are the potent inhibitors of urease. The IC50 (ranging in between 110 and 440 nM) values were higher as compared to that of standard, i.e., thiourea (IC50 = 490 ± 10 nM). The synthesized compounds were docked at the active sites of the Jack bean urease enzyme in order to explore the possible binding interactions of enzyme-ligand complexes; the results reinforced the in vitro biological activity results.

The Total Synthesis of Chondrochloren†A.

The first total synthesis of chondrochloren A is accomplished using a 1,2-metallate rearrangement addition as an alternative for the Nozaki-Hiyama-Kishi reaction. This transformation also avoids the inherent challenges of this polyketide segment and provides a new, unprecedented strategy to assemble polyketidal frameworks. The formation of the Z-enamide is accomplished using a Z-selective cross coupling of the corresponding amide to a Z-vinyl bromide.

Desymmetrization of C2 -Symmetric Bis(Boronic Esters) by Zweifel Olefinations.

anti-Configured 1,3-dimethyl deoxypropionate motifs are important sub structures in natural products. Herein, we describe a bidirectional approach for the rapid construction of natural products featuring such motifs by using C2 -symmetrical 1,3-bis(boronic esters). As for its application in convergent syntheses it was important to establish a selective mono-Zweifel olefination we describe the scope and limitations by using different 1,3-bis(boronic esters) and nucleophiles. This protocol takes advantage of the combination of the Hoppe-Matteson-Zweifel chemistry, which was elegantly put into practice by Aggarwal et al. In order to show its applicability the total syntheses of two natural products, serricornin and (+)-invictolide, were performed.

Contiguous Quaternary Carbons: A Selection of Total Syntheses.

Contiguous quaternary carbons in terpene natural products remain a major challenge in total synthesis. Synthetic strategies to overcome this challenge will be a pivotal prerequisite to the medicinal application of natural products and their analogs or derivatives. In this review, we cover syntheses of natural products that exhibit a dense assembly of quaternary carbons and whose syntheses were uncompleted until recently. While discussing their syntheses, we not only cover the most recent total syntheses but also provide an update on the status quo of modern syntheses of complex natural products. Herein, we review (±)-canataxpropellane, (+)-waihoensene, (-)-illisimonin A and (±)-11-O-debenzoyltashironin as prominent examples of natural products bearing contiguous quaternary carbons.

Towards the total synthesis of chondrochloren A: synthesis of the (Z)-enamide fragment.

The stereoselective synthesis of the (Z)-enamide fragment of chondrochloren (1) is described. A Buchwald-type coupling between amide 3 and (Z)-bromide 4 was used to generate the required fragment. The employed amide 3 comprising three chiral centers was obtained through a seven-step sequence starting from ᴅ-ribonic acid-1,4-lactone. The (Z)-vinyl bromide 4 is accessible in four steps from 4-hydroxybenzaldehyde. The pivotal cross coupling between both fragments was achieved after extensive experimentation with copper(I) iodide, K2CO3 and N,N'-dimethylethane-1,2-diamine.

Polyoxygenated Tertiary Alcohols: A Kiyooka Approach.

A Kiyooka aldol approach for the stereoselective synthesis of tertiary alcohols is presented. This approach allows for the incorporation of different substituents at all three remaining positions at the chiral center bearing the tertiary alcohol. To demonstrate the validity of this approach different chiral alcohols were depicted and the relationship of double bond geometry of the ketene acetal and the diastereoselectivity was established.

Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1n-3 DPA.

New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1n-3 DPA has been achieved using the underutilized sp3 -sp3 Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor. As such, this endogenous natural product is a lead compound for the development of novel immunoresolvents.

Synthesis of sulfonamide, amide and amine hybrid pharmacophore, an entry of new class of carbonic anhydrase II inhibitors and evaluation of chemo-informatics and binding analysis.

Selective inhibition of carbonic anhydrase (CA) enzyme is an active area of research for medicinal chemists. In the current account, a hybrid pharmacophore approach was employed to design sulfonamide, amide and amine containing new series of potent carbonic anhydrase II inhibitors. The aromatic fragment associated with pharmacophore was altered suitably in order to find effective inhibitors of CA-II. All the derivatives 4a-4m showed better inhibition compared to the standard acetazolamide. In particular, compound 4l exhibited significant inhibition with IC50 value of 0.01796 ±â€¯0.00036 µM. The chemo-informatics analysis justified that all the designed compounds possess <10 HBA and <5 HBD. The ligands-protein binding analyses showed that 4l confined in the active binding pocket with three hydrogen bonds observed with His63, Asn66 and Thr197 residues.

Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis.

It is a challenging objective in synthetic organic chemistry to create efficient access to biologically active compounds. In particular, one structural element which is frequently incorporated into the framework of complex natural products is a ß-hydroxy ketone. In this context, the aldol reaction is the most important transformation to generate this structural element as it not only creates new C-C bonds but also establishes stereogenic centers. In recent years, a large variety of highly selective methodologies of aldol and aldol-type reactions have been put forward. In this regard, the vinylogous Mukaiyama aldol reaction (VMAR) became a pivotal transformation as it allows the synthesis of larger fragments while incorporating 1,5-relationships and generating two new stereocenters and one double bond simultaneously. This review summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the vinylogous Mukaiyama aldol (VMA) reaction. This manuscript comprehensively condenses the last four years of research, covering the period 2016-2019.

The Rickiols: 20-, 22-, and 24-membered Macrolides from the Ascomycete Hypoxylon rickii.

In preceding studies the neotropical ascomycete Hypoxylon rickii turned out to be a prolific source of new secondary metabolites, considering that we had obtained terpenoids with five different scaffolds along with a series of terphenyls. From the mycelial extracts of a 70 L scale fermentation of this strain we additionally isolated nine new macrolides (1-9) by RP-HPLC. The planar structures were elucidated by NMR spectroscopy complemented by HR-ESIMS. The relative configurations were assigned by J-based configuration analyses and confirmed by Kishi's Universal Database. Subsequently, the absolute configurations were assigned by Mosher's method using the shift analysis of a tetra-MTPA derivative. For rickiol A (1) and E (5) we observed transesterification of 20-membered ring structures to 22-membered isomers rickiol A2 (6) and E2 (7), and to 24-membered isomers rickiol A3 (8) and rickiol E3 (9), respectively. Cytotoxic effects and moderate antibiotic activity against Gram-positive bacteria were observed for 1-8 and 1-6 and 8, respectively. The total synthesis of rickiol E3 (9) established easier access to these compounds.

Painting argyrins blue: Negishi cross-coupling for synthesis of deep-blue tryptophan analogue ß-(1-azulenyl)-l alanine and its incorporation into argyrin C.

The argyrins are a family of non-ribosomal peptides that exhibits different biological activities through only small structural changes. Ideally, a biologically active molecule can be tracked and observed in a variety of biological and clinical settings in a non-invasive manner. As a step towards this goal, we report here a chemical synthesis of unnatural deep blue amino acid ß-(1-azulenyl)-l alanine with different fluorescence and photophysical properties, which allows a spectral separation from the native tryptophan signal. This might be especially useful for cell localization studies and visualizing the targeted proteins. In particular, the synthesis of ß-(1-azulenyl)-l alanine was achieved through a Negishi coupling which proved to be a powerful tool for the synthesis of unnatural tryptophan analogs. Upon ß-(1-azulenyl)-l alanine incorporation into argyrin C, deep blue octapeptide variant was spectrally and structurally characterized.