The chiral TRIP anion combined with a simple commercially available palladacycle furnishes a highly active catalyst for the enantioselective rearrangement of allylic imidates to the corresponding ...amide products in high yields (see scheme). The stereoselectivity is induced entirely by the chiral phosphate anion although the catalyst complex contains a chiral palladacycle (see scheme).
Antibody-drug conjugates (ADCs) allow selective targeting of cytotoxic drugs to cancer cells presenting tumor-associated surface markers, thereby minimizing systemic toxicity. Traditionally, the drug ...is conjugated nonselectively to cysteine or lysine residues in the antibody. However, these strategies often lead to heterogeneous products, which make optimization of the biological, physical, and pharmacological properties of an ADC challenging. Here we demonstrate the use of genetically encoded unnatural amino acids with orthogonal chemical reactivity to synthesize homogeneous ADCs with precise control of conjugation site and stoichiometry. p -Acetylphenylalanine was site-specifically incorporated into an anti-Her2 antibody Fab fragment and full-length IgG in Escherichia coli and mammalian cells, respectively. The mutant protein was selectively and efficiently conjugated to an auristatin derivative through a stable oxime linkage. The resulting conjugates demonstrated excellent pharmacokinetics, potent in vitro cytotoxic activity against Her2 ⁺ cancer cells, and complete tumor regression in rodent xenograft treatment models. The synthesis and characterization of homogeneous ADCs with medicinal chemistry-like control over macromolecular structure should facilitate the optimization of ADCs for a host of therapeutic uses.
Acetaldehyde, now a big contender: A silyl prolinol derivative was found to catalyze the first Michael addition of acetaldehyde with both aromatic and aliphatic nitroolefins in excellent ...enantioselectivities (see scheme, TMS=trimethylsilyl). The utility of the reaction is illustrated in the synthesis of three current pharmaceuticals and in the synthesis of an enantiopure 3‐monosubstituted pyrrolidine.
A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant ...Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.
Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity in the brain. However, little is known about the molecular mechanisms regulating hippocampal neural ...progenitor cells (NPCs) and whether their fate can be pharmacologically modulated to improve neural plasticity and regeneration. Here, we report the characterization of a small molecule (KHS101) that selectively induces a neuronal differentiation phenotype. Mechanism of action studies revealed a link of KHS101 to cell cycle exit and specific binding to the TACC3 protein, whose knockdown in NPCs recapitulates the KHS101-induced phenotype. Upon systemic administration, KHS101 distributed to the brain and resulted in a significant increase in neuronal differentiation in vivo. Our findings indicate that KHS101 accelerates neuronal differentiation by interaction with TACC3 and may provide a basis for pharmacological intervention directed at endogenous NPCs.
Synthesis of 2,4-disubstituted quinolines has been achieved in a one-pot reaction from an aryl amine, an aldehyde and a terminal alkyne using CuCl (30 mol%) as a catalyst.
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Catalytic, asymmetric conjugate addition of carbamates to enoyl systems has been realized for the first time, providing a two-step access to virtually enantiopure N-protected β-amino acids.
A mild, efficient and expeditious method has been developed for the chemoselective conversion of aldehydes to the corresponding acylals in excellent yields, using acetic anhydride in the presence of ...catalytic amount (0.01–0.1
mol%) of In(OTf)
3. Ketones remain unaffected under the reaction condition. In(OTf)
3 can be recovered and reused without any loss of its catalytic activity.
A mild, efficient and expeditious method has been developed for the chemoselective conversion of aldehydes to the corresponding acylals in excellent yields, using acetic anhydride in the presence of catalytic amount (0.01–0.1
mol%) of In(OTf)
3. Ketones remain unaffected under the reaction condition. In(OTf)
3 can be recovered and reused without any loss of its catalytic activity.
In this era of rapid technological advancement, computer vision in medical analysis and diagnosis has a profound significance in detecting and classifying anomalies or diseases in the human body. ...This study proposes an ensemble learning method to classify brain tumors or neoplasms (i.e. glioma, meningioma, pituitary adenoma) and auto-immune disease lesion (i.e. multiple sclerosis) using magnetic resonance imaging (MRI) of brain tumors and multiple sclerosis patients. The method includes pre-processing, feature extraction, feature selection, and classification. The pre-processing phase uses region of interest (ROI) of both tumor and lesion, Collewet normalization, and Lloyd-max quantization. The base learner is designed with a support vector machine (SVM) classifier and prediction model with majority voting. Our proposed system operates well in contrast to other state-of-the-art methods, with the weighted sensitivity, specificity, precision, and accuracy of 97.5%, 98.838%, 98.011%, and 98.719%, respectively. Experimental results also show that the overall training and testing accuracy of our proposed model are 97.957% and 97.744% respectively. The findings may infer an unprecedented step for detecting the presence of lesions coexisting with the tumors in neuro-medicine diagnosis.
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Hooray aza‐Henry! A combination of zinc triflate, an amine base, and (−)‐N‐methylephedrine (NME), which can be easily recovered and reused, leads to high enantioselectivities in the aza‐Henry ...reaction of N‐Boc‐protected aldimines and nitromethane (see scheme; Boc=tert‐butyloxycarbonyl).
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