9 research outputs found
Pyridone functionalization: regioselective deprotonation of 6-methylpyridin-2(1H)- and -4(1H)-one derivatives
Selective functionalization at the α-methyl group of 1-substituted pyridin-2(1H)- and 4(1H)-ones (2- and 4-pyridones) can be achieved by appropriate choice of base. n-Butyllithium was found to effect clean 6(2)-methyl deprotonation of 1-benzyl-2- and -4-pyridone derivatives, while potassium hexamethyldisilazide (KHMDS) was the preferred reagent for methyl deprotonation of the corresponding 1-methyl-2- and -4-pyridones. Deprotonation proceeds smoothly at –78 °C, and the resulting anions react readily with a wide range of electrophiles (aldehydes, ketones, alkylating reagents, and an azo compound) under precise temperature control to form usefully functionalized 2- and 4-pyridones and quinolizinones
Isolation and structure determination of the first example of the azeto[2,3-c]quinolizinedione ring system
An unexpected azeto[2,3-c]quinolizinedione has been isolated during synthetic studies on the base catalyzed condensation of ethyl 6-methylpyridin-2(1H)-on-1-ylacetate with benzil. Closure of a fused four-membered azetidinone ring occurred when potassium hexamethyldisilazide was employed as the base. The structure of the product was confirmed by synchrotron X-ray crystallography. A possible mechanism for the formation of the product is considered
Novel and Versatile Synthesis of Disubstituted 1,2-Dihydro-1,2,4-triazol-3-ones
A novel method for the synthesis of a wide range of 1,5-disubstituted
1,2-dihydro-1,2,4-triazol-3-ones is described. The key step involves
a reaction between a dilithiated BOC-hydrazine and a <i>N</i>-alkoxycarbonylcarboximidothioate. A broad range of aryl and alkyl
functional groups are tolerated, providing a versatile route for the
synthesis of triazolones
Novel and Versatile Synthesis of Disubstituted 1,2-Dihydro-1,2,4-triazol-3-ones
A novel method for the synthesis of a wide range of 1,5-disubstituted
1,2-dihydro-1,2,4-triazol-3-ones is described. The key step involves
a reaction between a dilithiated BOC-hydrazine and a <i>N</i>-alkoxycarbonylcarboximidothioate. A broad range of aryl and alkyl
functional groups are tolerated, providing a versatile route for the
synthesis of triazolones
Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors To Explore a MEK Resistance Hypothesis
Potent
and selective inhibitors of Dyrk1B kinase were developed
to explore the hypothesis, based on siRNA studies, that Dyrk1B may
be a resistance mechanism in cells undergoing a stress response
Diverse Heterocyclic Scaffolds as Allosteric Inhibitors of AKT
Wide-ranging exploration of potential replacements for
a quinoline-based
inhibitor of activation of AKT kinase led to number of alternative,
novel scaffolds with potentially improved potency and physicochemical
properties. Examples showed predictable DMPK properties, and one such
compound demonstrated pharmacodynamic knockdown of phosphorylation
of AKT and downstream biomarkers in vivo and inhibition of tumor growth
in a breast cancer xenograft model
Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2
The RAS/RAF/MEK/ERK signaling pathway
has been targeted with a
number of small molecule inhibitors in oncology clinical development
across multiple disease indications. Importantly, cell lines with
acquired resistance to B-RAF and MEK inhibitors have been shown to
maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors.
There are a number of selective, noncovalent ERK1/2 inhibitors reported
along with the promiscuous hypothemycin (and related analogues) that
act via a covalent mechanism of action. This article reports the identification
of multiple series of highly selective covalent ERK1/2 inhibitors
informed by structure-based drug design (SBDD). As a starting point
for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical
series identified via high-throughput screening were exploited. These
approaches resulted in the identification of selective covalent tool
compounds for potential <i>in vitro</i> and <i>in vivo</i> studies to assess the risks and or benefits of targeting this pathway
through such a mechanism of action
Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation
Constitutively
active mutant KRas displays a reduced rate of GTP
hydrolysis via both intrinsic and GTPase-activating protein-catalyzed
mechanisms, resulting in the perpetual activation of Ras pathways.
We describe a fragment screening campaign using X-ray crystallography
that led to the discovery of three fragment binding sites on the Ras:SOS
complex. The identification of tool compounds binding at each of these
sites allowed exploration of two new approaches to Ras pathway inhibition
by stabilizing or covalently modifying the Ras:SOS complex to prevent
the reloading of Ras with GTP. Initially, we identified ligands that
bound reversibly to the Ras:SOS complex in two distinct sites, but
these compounds were not sufficiently potent inhibitors to validate
our stabilization hypothesis. We conclude by demonstrating that covalent
modification of Cys118 on Ras leads to a novel mechanism of inhibition
of the SOS-mediated interaction between Ras and Raf and is effective
at inhibiting the exchange of labeled GDP in both mutant (G12C and
G12V) and wild type Ras
Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point
There are a number of small-molecule
inhibitors targeting the RAS/RAF/MEK/ERK
signaling pathway that have either been approved or are in clinical
development for oncology across a range of disease indications. The
inhibition of ERK1/2 is of significant current interest, as cell lines
with acquired resistance to BRAF and MEK inhibitors have been shown
to maintain sensitivity to ERK1/2 inhibition in preclinical models.
This article reports on our recent work to identify novel, potent,
and selective reversible ERK1/2 inhibitors from a low-molecular-weight,
modestly active, and highly promiscuous chemical start point, compound <b>4</b>. To guide and inform the evolution of this series, inhibitor
binding mode information from X-ray crystal structures was critical
in the rapid exploration of this template to compound <b>35</b>, which was active when tested in in vivo antitumor efficacy experiments