ABSTRACT
Recent advances in computer vision (CV) and natural language processing have been driven by exploiting big data on practical applications. However, these research fields are still limited by the sheer volume, versatility, and diversity of the available datasets. CV tasks, such as image captioning, which has primarily been carried out on natural images, still struggle to produce accurate and meaningful captions on sketched images often included in scientific and technical documents. The advancement of other tasks such as 3D reconstruction from 2D images requires larger datasets with multiple viewpoints. We introduce DeepPatent2, a large-scale dataset, providing more than 2.7 million technical drawings with 132,890 object names and 22,394 viewpoints extracted from 14 years of US design patent documents. We demonstrate the usefulness of DeepPatent2 with conceptual captioning. We further provide the potential usefulness of our dataset to facilitate other research areas such as 3D image reconstruction and image retrieval.
ABSTRACT
Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent inâ vitro and inâ vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.
Subject(s)
Antitubercular Agents/chemistry , Bacterial Proteins/metabolism , Cytochrome P-450 CYP2C9/metabolism , Mycobacterium tuberculosis/metabolism , Thiophenes/chemistry , Animals , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Bacterial Proteins/antagonists & inhibitors , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Cytochrome P-450 CYP2C9/chemistry , Drug Resistance, Bacterial/drug effects , Mice , Microbial Sensitivity Tests , Molecular Dynamics Simulation , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship , Thiophenes/pharmacology , Thiophenes/therapeutic use , Tuberculosis/drug therapy , Tuberculosis/veterinaryABSTRACT
A library of benzimidazole-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-substituted aryl- and heteroaryltrifluoroborates with aromatic 1,2-diamines under oxidative conditions. The efficient Suzuki-Miyaura cross-coupling of products thus formed to various aryl and heteroaryl bromides was achieved in good yields. The method allows the facile preparation of benzimidazole-containing triaromatic products in two steps from simple potassium formyl substituted aryl- or heteroaryltrifluoroborates.
Subject(s)
Benzimidazoles/chemical synthesis , Borates/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Potassium/chemistry , Benzimidazoles/chemistry , Borates/chemistry , Catalysis , Combinatorial Chemistry Techniques , Diamines/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
A protected cyclitol aglycon was tethered to an (N-arylsulfonyl)glucosamine donor by a methylene linker; the exclusively alpha-selective intramolecular glycosylation reaction was then initiated by electrophilic activation of the thioglycoside donor portion. Further transformations of the glycosylation product to give the M. tuberculosis detoxifier mycothiol and its oxidized congener, the disulfide mycothione, are detailed.
Subject(s)
Cysteine/chemical synthesis , Glycopeptides/chemical synthesis , Inositol/chemical synthesis , Catalysis , Cysteine/chemistry , Glucosamine/chemistry , Glycopeptides/chemistry , Glycosylation , Inositol/chemistry , Molecular Structure , Mycobacterium tuberculosis/chemistry , Nuclear Magnetic Resonance, Biomolecular , Stereoisomerism , Thioglycosides/chemical synthesis , Thioglycosides/chemistryABSTRACT
The potent O-GlcNAcase (OGA) inhibitor GlcNAc-thiazoline has been modified by buffer- or acylation-induced imine-to-enamine conversion and then electrophile or radical addition (Xn = D3, F, N3, OH, SMe, COCF3, CF3). Several functionalized GlcNAc-thiazolines show highly selective inhibition of OGA vs human hexosaminidase and thus have promise as tools for targeted investigations of OGA, an enzyme linked to diabetes and neurodegeneration. A new radical addition/fragmentation reaction of the N-(trifluoroacetyl)enamine has been discovered.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Glucosamine/analogs & derivatives , Thiazoles/chemical synthesis , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/radiation effects , Free Radicals/chemical synthesis , Free Radicals/pharmacology , Free Radicals/radiation effects , Glucosamine/chemical synthesis , Glucosamine/pharmacology , Glucosamine/radiation effects , Hexosaminidases/antagonists & inhibitors , Humans , Isomerism , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Thiazoles/pharmacology , Thiazoles/radiation effects , beta-N-Acetylhexosaminidases/antagonists & inhibitorsABSTRACT
The O,O-dibenzyl-S-glycosyl phosphothioite derived from 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-1-thio-alpha-D-glucopyranose rearranges under the influence of triethylborane and air to provide the corresponding 1-C-pyranosyl-O,O-dibenzylphosphonothioate, a new type of carbohydrate derivative. The isomeric beta phosphothioite is compared, and evidence of a radical chain mechanism for the Pudovik rearrangement is presented.
