Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium-Catalyzed Enantio-, Chemo- and Diastereoselective Methylene C(sp3)-H arylation.

The enantioselective desymmetrizing C-H activation of α-gem-dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp3)-H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo- and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,ß-contiguous stereogenic centers via PdII-catalyzed asymmetric arylation of unbiased methylene C(sp3)-H, in good yields and with high levels of enantio-, chemo- and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem-dialkyl groups with two different aryl iodides, giving a range of ß-Ar1-ß'-Ar2-aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.

Pd(II)-Catalyzed Tandem Enantioselective Methylene C(sp3 )-H Alkenylation-Aza-Wacker Cyclization to Access ß-Stereogenic γ-Lactams.

Herein, we describe an unprecedented cascade reaction to ß-stereogenic γ-lactams involving Pd(II)-catalyzed enantioselective aliphatic methylene C(sp3 )-H alkenylation-aza-Wacker cyclization through syn-aminopalladation. Readily available 3,3'-substituted BINOLs are used as chiral ligands, providing the corresponding γ-lactams with broad scope and high enantioselectivities (up to 98 % ee).

Total Synthesis of (+)- and (±)-Hosieine†A.

Described herein is a concise total synthesis of the highly potent nicotinic acetylcholine receptor ligand hosieine A in racemic and enantioenriched forms. The synthesis requires only seven steps and features a telescoped reaction sequence initiated by a gold-catalyzed Rautenstrauch reaction.

Synthetic studies toward the citrinadins: enantioselective preparation of an advanced spirooxindole intermediate.

This manuscript describes the enantioselective preparation of a spirooxindole that is suited for advancedment to either Citrinadin A or B.

A Porphyrinic Metal-Organic Framework with Cooperative Adsorption Domains for PFAS Removal from Water.

The removal of toxic poly- and perfluoroalkyl substances (PFAS) as persistent pollutants from wastewater is imperative but challenging for water remediation. Many adsorbents including activated carbon, biochar, and clay minerals have been investigated for PFAS removal, but most of these materials are faced with high cost or/and low efficiency. The use of metal-organic frameworks (MOFs) as sorbents is attractive for efficient removal of PFAS due to their tailor-made structures and high surface areas. Herein, we synthesized, characterized a water stable Zr-based porphyrinic MOF (PCN-224) with cooperative adsorption domains, and demonstrated its excellent capture performance toward perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS) and perfluorobutane sulfonate (PFBS). PCN-224 has maximum uptake capacities of 963, 517, and 395 mg g-1 for PFOS, PFHxS, and PFBS, respectively, which are much higher than that of granular activated carbon. Moreover, coexistent anions (Cl-, SO4 2-) and humic acid have negligible effects on PFOS adsorption. The excellent adsorption performance of PCN-224 toward PFOS is due to the orthogonal cationic channel pores with a diameter of 1.9 nm, the hydrophobic porphyrin units, and the Zr6 clusters with acidic sites. PCN-224 can be readily regenerated and reused. This work highlights the potential of MOFs with multiple adsorption domains for water remediation.

An enantioselective total synthesis and stereochemical revision of (+)-citrinadin B.

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A-C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step.

Evidence of potential Campylobacter jejuni zooanthroponosis in captive macaque populations.

Non-human primates share recent common ancestry with humans and exhibit comparable disease symptoms. Here, we explored the transmission potential of enteric bacterial pathogens in monkeys exhibiting symptoms of recurrent diarrhoea in a biomedical research facility in China. The common zoonotic bacterium Campylobacter jejuni was isolated from macaques (Macaca mulatta and Macaca fascicularis) and compared to isolates from humans and agricultural animals in Asia. Among the monkeys sampled, 5 % (44/973) tested positive for C. jejuni, 11 % (5/44) of which displayed diarrhoeal symptoms. Genomic analysis of monkey isolates, and 1254 genomes from various sources in Asia, were used to identify the most likely source of human infection. Monkey and human isolates shared high average nucleotide identity, common MLST clonal complexes and clustered together on a phylogeny. Furthermore, the profiles of putative antimicrobial resistance genes were similar between monkeys and humans. Taken together these findings suggest that housed macaques became infected with C. jejuni either directly from humans or via a common contamination source.

SULT1A1-dependent sulfonation of alkylators is a lineage-dependent vulnerability of liver cancers.

Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the second leading cause of cancer-related deaths worldwide. Most individuals are treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for selection. Here using high-throughput screens, proteomics and in vitro resistance models, we identify the small molecule YC-1 as selectively active against a defined subset of cell lines derived from both liver cancer types. We demonstrate that selectivity is determined by expression of the liver-resident cytosolic sulfotransferase enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA-binding factors. Computational analysis defined a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small-molecule class. These studies provide a foundation for preclinical development of these agents and point to the broader potential of exploiting SULT1A1 activity for selective targeting strategies.

Total synthesis of the spirocyclic imine marine toxin (-)-gymnodimine and an unnatural C4-epimer.

The first total synthesis of the marine toxin (-)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels-Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki-Hiyama-Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide, and a few additional steps provided (-)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.

Staurosporine Analogs Via C-H Borylation.

Staurosporine is among the most potent naturally occurring kinase inhibitors isolated to date and has served as a lead compound for numerous drug development efforts in several therapeutic areas. Herein we report that C-H borylation chemistry provides access to analogs of staurosporine that were previously inaccessible to medicinal chemists who, in the past four decades, have prepared over 1000 semisynthetic staurosporine analogs.

Missed diagnosis of femoral deep artery rupture after femoral shaft fracture: A case report.

BACKGROUND: Vascular injury is a rare complication of femoral shaft fractures, and rupture of the deep femoral artery is more difficult to diagnose because of its anatomical location and symptoms. Despite its low incidence, deep femoral artery rupture can lead to life-threatening outcomes, such as compartment syndrome, making early identification and diagnosis critical. CASE SUMMARY: A 45-year-old male patient was admitted to our hospital due to right lower limb trauma in a car accident, with complaints of severe pain and swelling on his right thigh. X-ray demonstrated a right femoral shaft fracture. During preparation for emergency surgery, his blood pressure and blood oxygen saturation dropped, and sensorimotor function was lost. Computed tomography angiography was performed immediately to confirm the diagnosis of rupture of the deep femoral artery and compartment syndrome, so fasciotomy and vacuum-assisted closure were performed. Rhabdomyolysis took place after the operation and the patient was treated with appropriate electrolyte correction and diuretic therapy. Twenty days after the fasciotomy, treatment with the Hoffman Type II External Fixation System was planned, but it was unable to be immobilized internally based on a new esophageal cancer diagnosis. We kept the external fixation for 1 year, and 3 years of follow-up showed improvement of the patient's overall conditions and muscle strength. CONCLUSION: For patients with thigh swelling, pain, anemia, and unstable vital signs, anterior femoral artery injury should be highly suspected. Once diagnosed, surgical treatment should be performed immediately and complications of artery rupture must be suspected and addressed in time.

The Novel Protein Cj0371 Inhibits Chemotaxis of Campylobacter jejuni.

cj0371 is a novel gene that is associated with Campylobacter jejuni virulence, and an isogenic mutant of cj0371 showed hyper chemotaxis and motility. Chemotactic motility is an important virulence factor and is involved in C. jejuni pathogenesis. Campylobacter sp. has specific variations of the common chemotaxis components, including histidine autokinase CheA, coupling scaffold protein CheV, chemotaxis response regulator protein CheY and several chemoreceptor proteins. In this study, we used immunoprecipitation combined with LC-MS/MS analyses to screen six chemotaxis pathway proteins that potentially interact with the putative protein Cj0371. qRT-PCR was used to quantitatively analyze the expression of these chemotaxis genes and basic flagella genes. The results showed that the expression of cheV, cj1110c, and cj0262c was significantly up-regulated, and four flagella genes also had up-regulated expression in the cj0371 mutant. GST pull-down analyses found that Cj0371 interacted with the receiver domain of the CheV protein. Enzyme-coupled spectrophotometric assays showed that the ATPase activity of CheA was higher when Cj0371 was not present in the chemotaxis reaction medium. Therefore, we concludes that cj0371 has a negative influence on C. jejuni chemotaxis, which may occur by adjusting the receiver domain of CheV to influence chemotaxis. This paper provides a new component in the chemotaxis pathway of C. jejuni for the first time and highlight the complexity of this remarkable pathway.

Diastereoselective, vinylogous mukaiyama aldol additions of silyloxy furans to cyclic ketones: annulation of butenolides and gamma-lactones.

[reaction: see text] Vinylogous Mukaiyama aldol reactions employing silyloxyfurans and substituted cyclic ketones are described. These annulations proceed with moderate to good diastereoselectivity. The potential application of this process to the synthesis of butenolide and gamma-lactone containing natural products was demonstrated by further transformations of the addition products.

Synthetic studies toward citrinadin A: construction of the pentacyclic core.

This manuscript describes the preparation of an advanced intermediate toward the total synthesis of citrinadin A, featuring a [3+2] cycloaddition employing in situ generation of the dipole.

Studies toward a marine toxin immunogen: enantioselective synthesis of the spirocyclic imine of (-)-gymnodimine.

[reaction: see text] An enantioselective Diels-Alder reaction catalyzed by an Evans' copper-bis(oxazoline) complex was utilized to construct a highly functionalized spirolactam, a key intermediate in our projected total synthesis of the marine toxin, gymnodimine. Additional transformations, including a mild N-tosyl group deprotection, afforded a keto spirocyclic imine moiety, the proposed pharmacophore of gymnodimine. Thus, the prepared ketone is a potentially useful intermediate for conjugation to provide an immunogen for eventual monitoring of gymnodimine and congeners.

Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint.

The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 µM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 µM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN → σ*S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.