1,723,612 research outputs found
Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036
No full textA chromatography-free
asymmetric synthesis of GDC-6036 (1) was achieved via
a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl]2 and 1 mol % (R,R)-Chiraphite
to afford the key intermediate (Ra)-3. An alkoxylation of (Ra)-3 with (S)-N-methylprolinol
(4) and a global deprotection generates the penultimate
heterobiaryl intermediate 2. A controlled acrylamide
installation by stepwise acylation/sulfone elimination and final adipate
salt formation and crystallization delivered high-purity GDC-6036
(1)
Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036
No full textAn efficient asymmetric synthesis of a potent KRAS G12C
covalent
inhibitor, GDC-6036 (1), is reported. The synthesis features
a highly atroposelective Negishi coupling to construct the key C–C
bond between two highly functionalized pyridine and quinazoline moieties
by employing a Pd/Walphos catalytic system. Statistical modeling by
comparing computational descriptors of a range of Walphos chiral bisphosphine
ligands to a training set of experimental results was used to inform
the selection of the best ligand, W057-2, which afforded
the desired Negishi coupling product (Ra)-3 in excellent selectivity.
A subsequent telescoped reaction sequence of alkoxylation, global
deprotection, and acrylamide formation, followed by a final adipate
salt formation, furnished GDC-6036 (1) in 40% overall
yield from starting materials pyridine 5 and quinazoline 6
NS 6036, hibrid kukuruza
No full textOvo je novostvoreni hibrid kukuruza (Zea mays L.) NS 6036 priznat od strane Uprave za zaštitu bilja Ministarstva poljoprivrede, šumarstva i vodoprivrede Republike Srbije.This is registered newly-developed hybrid of maize (Zea mays L.) NS 6036 released by the Plant Protection Directorate of the Ministry of Agriculture, Forestry and Water Management of the Republic of Serbia.Broj rešenja: 320-04-02751/2/2020-11
Datum rešenja: 04.03.2022
Binding modes of the KRAS(G12C) inhibitors GDC-6036 and LY3537982 revealed by all atom molecular dynamics simulations
No full textAlmost 80 co-crystal structures of KRAS switch-II pocket (SII-P) targeting inhibitors are currently available in the RCSB Protein Data Bank. These publicly available structures are invaluable tools that have led to a more in-depth understanding of KRAS SII-P pocket, which is crucial for targeted drug design efforts. The binding modes (co-crystal structures) of two KRAS(G12C) inhibitors that have advanced to the clinical trials, GDC-6036 (divarasib) and LY3537982, are currently unavailable. Here, we reveal the putative binding modes of these two G12C inhibitors by utilizing the available structural data of analogous compounds and molecular dynamics (MD) simulations (total simulation time of 200 µs). Furthermore, we analyzed the energetical barrier related to their atropisomer interconversion by quantum mechanics (QM) calculations. Finally, biochemical assays supported our in silico observations, revealing remarkably high affinity for both inhibitors towards KRAS(G12C), which is, however, sacrificed by a co-mutation at Tyr96 (GDC-6036, LY3537982) or His95 (GDC-6036)
Block Card 6036 Livingston Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Dwelling | 6036 Livingston Drive (Toledo, Ohio) | Ranch houses | Hopewell Acres (Toledo, Ohio) | Greenwood Area (Toledo, Ohio) | West Toledo Area (Toledo, Ohio
Block Card 6036 Katherine Avenue
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Garrison colonial | 6036 Katherine Avenue (Toledo, Ohio) | Dwelling | Chestnut Estates Addtion | Greenwood Park Area (Toledo, Ohio
Block Card 6036 Van Wormer Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Dwelling | 6036 Van Wormer Drive (Toledo, Ohio) | Cape Cod Style | Hopewell Hills (Toledo, Ohio) | Greenwood Area (Toledo, Ohio) | West Toledo Area (Toledo, Ohio
Liquid flows in microchannels
No full textMade available in DSpace on 2021-11-04T16:28:21Z (GMT). No. of bitstreams: 2
TAM691-UILU-ENG-2000-6036.pdf: 11566432 bytes, checksum: ca9f924f87a571661d1e49f6d95aac46 (MD5)
license.txt: 4802 bytes, checksum: 58353f9dd6876860dd5221f3d7872a95 (MD5)
Previous issue date: 2000-1
Linked collectors and determiners for: The first record of the genus Eskemukerjea (Polygonaceae) from China.
No full textNatural history specimen data linked to collectors and determiners held within, "The first record of the genus Eskemukerjea (Polygonaceae) from China". Claims or attributions were made on Bionomia by volunteer Scribes, <a href="http://bionomia.net/dataset/e27cad37-6036-4407-8f23-dbbf217b1c20">https://bionomia.net/dataset/e27cad37-6036-4407-8f23-dbbf217b1c20</a> using specimen data from the dataset aggregated by the Global Biodiversity Information Facility, <a href="https://gbif.org/dataset/e27cad37-6036-4407-8f23-dbbf217b1c20">https://gbif.org/dataset/e27cad37-6036-4407-8f23-dbbf217b1c20</a>. Formatted as a Frictionless Data package
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