28 research outputs found
Stereoselective Sequential [4+2]/[2+2] Cycloadditions Involving 2‑Alkenylindolenines: An Approach to Densely Functionalized Benzo[<i>b</i>]indolizidines
A stereoselective sequential [4+2]/[2+2]
cycloaddition process
involving 2-alkenylindolenines has been developed. This unprecedented
protocol allows a rapid access to densely functionalized benzoÂ[<i>b</i>]Âindolizidines containing a fully substituted piperidine
ring with five contiguous stereogenic centers in good yields with
excellent diastereoselectivities. This finding demonstrated the unique
synthetic utility of the 2-alkenylindolenine species in the construction
of complex polycyclic <i>N</i>-heterocycles
Assembly of Indolenines, 3‑Amino Oxindoles, and Aldehydes into Indolenine-Substituted Spiro[pyrrolidin-2,3′-oxindoles] via 1,3-Dipolar Cycloaddition with Divergent Diastereoselectivities
A novel
one-pot 1,3-dipolar cycloaddition of indolenines, 3-aminooxindoles,
and aldehydes is reported. The reaction provides indolenine-substituted
spiroÂ[pyrrolidin-2,3′-oxindoles] containing four contiguous
stereogenic centers in high yields (up to 99%) and excellent diastereoselectivities
(up to >20:1 dr) under mild conditions. Remarkably, the inversion
of diastereoselectivity could be readily achieved through slightly
modifying the reaction conditions
Stereoselective Sequential [4+2]/[2+2] Cycloadditions Involving 2‑Alkenylindolenines: An Approach to Densely Functionalized Benzo[<i>b</i>]indolizidines
A stereoselective sequential [4+2]/[2+2]
cycloaddition process
involving 2-alkenylindolenines has been developed. This unprecedented
protocol allows a rapid access to densely functionalized benzoÂ[<i>b</i>]Âindolizidines containing a fully substituted piperidine
ring with five contiguous stereogenic centers in good yields with
excellent diastereoselectivities. This finding demonstrated the unique
synthetic utility of the 2-alkenylindolenine species in the construction
of complex polycyclic <i>N</i>-heterocycles
Stereoselective Sequential [4+2]/[2+2] Cycloadditions Involving 2‑Alkenylindolenines: An Approach to Densely Functionalized Benzo[<i>b</i>]indolizidines
A stereoselective sequential [4+2]/[2+2]
cycloaddition process
involving 2-alkenylindolenines has been developed. This unprecedented
protocol allows a rapid access to densely functionalized benzoÂ[<i>b</i>]Âindolizidines containing a fully substituted piperidine
ring with five contiguous stereogenic centers in good yields with
excellent diastereoselectivities. This finding demonstrated the unique
synthetic utility of the 2-alkenylindolenine species in the construction
of complex polycyclic <i>N</i>-heterocycles
Stereoselective Sequential [4+2]/[2+2] Cycloadditions Involving 2‑Alkenylindolenines: An Approach to Densely Functionalized Benzo[<i>b</i>]indolizidines
A stereoselective sequential [4+2]/[2+2]
cycloaddition process
involving 2-alkenylindolenines has been developed. This unprecedented
protocol allows a rapid access to densely functionalized benzoÂ[<i>b</i>]Âindolizidines containing a fully substituted piperidine
ring with five contiguous stereogenic centers in good yields with
excellent diastereoselectivities. This finding demonstrated the unique
synthetic utility of the 2-alkenylindolenine species in the construction
of complex polycyclic <i>N</i>-heterocycles
Discovery of a Novel Ketohexokinase Inhibitor with Improved Drug Distribution in Target Tissue for the Treatment of Fructose Metabolic Disease
Excessive
fructose absorption and its subsequent metabolisms are
implicated in nonalcoholic fatty liver disease, obesity, and insulin
resistance in humans. Ketohexokinase (KHK) is a primary enzyme involved
in fructose metabolism via the conversion of fructose to fructose-1-phosphate.
KHK inhibition might be a potential approach for the treatment of
metabolic disorders. Herein, a series of novel KHK inhibitors were
designed, synthesized, and evaluated. Among them, compound 14 exhibited more potent activity than PF-06835919 based
on the rat KHK inhibition assay in vivo, and higher drug distribution
concentration in the liver. Its good absorption, distribution, metabolism,
and excretion and pharmacokinetic properties make it a promising clinical
candidate
Additional file 1 of Genome-wide CRISPR screen identifies ESPL1 limits the response of gastric cancer cells to apatinib
Additional file 1: Fig. S1. Quantitative real-time PCR analysis the high expression levels of the candidate genes. a MCM2, CCND3, ESPL1, PLK1, TCF7, PRICKLE1 and VANGL1 mRNA level in AGS cells was detected after transfected with corresponding sgRNA; b MCM2, CCND3, ESPL1, PLK1, TCF7, PRICKLE1 and VANGL1 mRNA level in HGC27 cells was detected after transfected with corresponding sgRNA. Statistical significance was determined by One-way ANOVA. Data were represented as means ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the NC group
Discovery of a Novel Ketohexokinase Inhibitor with Improved Drug Distribution in Target Tissue for the Treatment of Fructose Metabolic Disease
Excessive
fructose absorption and its subsequent metabolisms are
implicated in nonalcoholic fatty liver disease, obesity, and insulin
resistance in humans. Ketohexokinase (KHK) is a primary enzyme involved
in fructose metabolism via the conversion of fructose to fructose-1-phosphate.
KHK inhibition might be a potential approach for the treatment of
metabolic disorders. Herein, a series of novel KHK inhibitors were
designed, synthesized, and evaluated. Among them, compound 14 exhibited more potent activity than PF-06835919 based
on the rat KHK inhibition assay in vivo, and higher drug distribution
concentration in the liver. Its good absorption, distribution, metabolism,
and excretion and pharmacokinetic properties make it a promising clinical
candidate
Asymmetric [3 + 2] Cycloaddition of 3‑Amino Oxindole-Based Azomethine Ylides and α,β-Enones with Divergent Diastereocontrol on the Spiro[pyrrolidine-oxindoles]
A general and practical
organocatalytic asymmetric 1,3-dipolar
cycloaddition of 3-amino oxindole-based azomethine ylides and α,β-enones
has been developed. This reaction delivered spiroÂ[pyrrolidine-2,3′-oxindole]
products in high yields with excellent regio- and enantioselectivities
(up to 99% yield, >20:1 rr, 99% <i>ee</i>). In addition,
an array of spiroÂ[dihydropyrrole-2,3′-oxindoles] were readily
accessed by oxidative dehydrogenation. Notably, the inversion of the
diastereoselectivity of the spiroÂ[pyrrolidine-oxindole] product could
be easily achieved through a facile oxidation–reduction process
An Organocatalytic Asymmetric Friedel–Crafts Addition/Fluorination Sequence: Construction of Oxindole–Pyrazolone Conjugates Bearing Vicinal Tetrasubstituted Stereocenters
A highly efficient
and practical one-pot sequential process, consisting
of an organocatalytic enantioselective Friedel–Crafts-type
addition of 4-nonsubstituted pyrazolones to isatin-derived <i>N</i>-Boc ketimines and a subsequent diastereoselective fluorination
of the pyrazolone moiety, is developed. This reaction sequence delivers
novel oxindole–pyrazolone adducts featuring vicinal tetrasubstituted
stereocenters with a 0.5 mol % catalyst loading in high yield with
excellent enantio- and diastereocontrol. Notably, chloro, bromo, and
thioether functionalities can be readily incorporated, rendering a
broad diversity of the product