7 research outputs found
Carbon鈥揅arbon Bond-Forming Reactions of 伪-Thioaryl Carbonyl Compounds for the Synthesis of Complex Heterocyclic Molecules
Strategies for the formation of carbon鈥揷arbon
bonds from
the 伪-thioaryl carbonyl products of substituted lactams are
described. Although direct functionalization is possible, a two step
process of oxidation and magnesium-sulfoxide exchange has proven optimal.
The oxidation step results in the formation of two diastereomers that
exhibit markedly different levels of stability toward elimination,
which is rationalized on the basis of quantum mechanical calculations
and X-ray crystallography. Treatment of the sulfoxide with <i>i</i>-PrMgCl results in the formation of a magnesium enolate
that will undergo an intramolecular Michael addition reaction to form
two new stereogenic centers. The relationship between the substitution
patterns of the sulfoxide substrate and the efficiency of the magnesium
exchange reaction are also described
Carbon鈥揅arbon Bond-Forming Reactions of 伪-Thioaryl Carbonyl Compounds for the Synthesis of Complex Heterocyclic Molecules
Strategies for the formation of carbon鈥揷arbon
bonds from
the 伪-thioaryl carbonyl products of substituted lactams are
described. Although direct functionalization is possible, a two step
process of oxidation and magnesium-sulfoxide exchange has proven optimal.
The oxidation step results in the formation of two diastereomers that
exhibit markedly different levels of stability toward elimination,
which is rationalized on the basis of quantum mechanical calculations
and X-ray crystallography. Treatment of the sulfoxide with <i>i</i>-PrMgCl results in the formation of a magnesium enolate
that will undergo an intramolecular Michael addition reaction to form
two new stereogenic centers. The relationship between the substitution
patterns of the sulfoxide substrate and the efficiency of the magnesium
exchange reaction are also described
Build/Couple/Pair Strategy for the Synthesis of Stereochemically Diverse Macrolactams via Head-to-Tail Cyclization
A build/couple/pair (B/C/P) strategy was employed to
generate a
library of 7936 stereochemically diverse 12-membered macrolactams.
All 8 stereoisomers of a common linear amine precursor were elaborated
to form the corresponding 8 stereoisomers of two regioisomeric macrocyclic
scaffolds via head-to-tail cyclization. Subsequently, these 16 scaffolds
were further diversified via capping of two amine functionalities
on SynPhase Lanterns. Reagents used for solid-phase diversification
were selected using a sparse matrix design strategy with the aim of
maximizing coverage of chemical space while adhering to a preset range
of physicochemical properties
A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells
The KRAS oncogene is found in up to 30% of all human
tumors. In
2009, RNAi experiments revealed that lowering mRNA levels of a transcript
encoding the serine/threonine kinase STK33 was selectively toxic to
KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors
of STK33 might selectively target KRAS-dependent cancers. To test
this hypothesis, we initiated a high-throughput screen using compounds
in the Molecular Libraries Small Molecule Repository (MLSMR). Several
hits were identified, and one of these, a quinoxalinone derivative,
was optimized. Extensive SAR studies were performed and led to the
chemical probe ML281 that showed low nanomolar inhibition of purified
recombinant STK33 and a distinct selectivity profile as compared to
other STK33 inhibitors that were reported in the course of these studies.
Even at the highest concentration tested (10 渭M), ML281 had
no effect on the viability of KRAS-dependent cancer cells. These results
are consistent with other recent reports using small-molecule STK33
inhibitors. Small molecules having different chemical structures and
kinase-selectivity profiles are needed to fully understand the role
of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable
addition to small-molecule probes of STK33
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described