5 research outputs found
Profiling and Application of Photoredox C(sp<sup>3</sup>)âC(sp<sup>2</sup>) Cross-Coupling in Medicinal Chemistry
Recent
visible-light photoredox catalyzed CÂ(sp<sup>3</sup>)âCÂ(sp<sup>2</sup>) cross-coupling provides a novel transformation to potentially
enable the synthesis of medicinal chemistry targets. Here, we report
a profiling study of photocatalytic CÂ(sp<sup>3</sup>)âCÂ(sp<sup>2</sup>) cross-coupling, both decarboxylative coupling and cross-electrophile
coupling, with 18 pharmaceutically relevant aryl halides by using
either Kessil lamp or our newly developed integrated photoreactor.
Integrated photoreactor accelerates reaction rate and improves reaction
success rate. Cross-electrophile coupling gives higher success rate
with broad substrate scope on alkyl halides than that of the decarboxylative
coupling. In addition, a successful application example on a discovery
program demonstrates the efficient synthesis of medicinal chemistry
targets via photocatalytic CÂ(sp<sup>3</sup>)âCÂ(sp<sup>2</sup>) cross-coupling by using our integrated photoreactor
Chemoselective Peptide Modification via Photocatalytic Tryptophan βâPosition Conjugation
Targeting tryptophan
is a promising strategy to achieve high levels
of selectivity for peptide or protein modification. A chemoselective
peptide modification method via photocatalytic tryptophan β-position
conjugation has been discovered. This transformation has good substrate
scope for both peptide and Michael acceptor, and has good chemoselectivity
versus other amino acid residues. The endogenous peptides, glucagon
and GLP-1 amide, were both successfully conjugated at the tryptophan
β-position. Insulin was studied as a nontryptophan control molecule,
resulting in exclusive B-chain C-terminal-selective decarboxylative
conjugation. This transformation provides a novel approach toward
peptide modification to support the discovery of new therapeutic peptides,
protein labeling and bioconjugation
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A General Small-Scale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions
Photocatalysis for
organic synthesis has experienced an exponential
growth in the past 10 years. However, the variety of experimental
procedures that have been reported to perform photon-based catalyst
excitation has hampered the establishment of general protocols to
convert visible light into chemical energy. To address this issue,
we have designed an integrated photoreactor for enhanced photon capture
and catalyst excitation. Moreover, the evaluation of this new reactor
in eight photocatalytic transformations that are widely employed in
medicinal chemistry settings has confirmed significant performance
advantages of this optimized design while enabling a standardized
protocol
Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinylâ1<i>H</i>âbenzimidazole Diacylglycerol Acyltransferase 1 Inhibitors
Miniaturization and parallel processing
play an important role
in the evolution of many technologies. We demonstrate the application
of miniaturized high-throughput experimentation methods to resolve
synthetic chemistry challenges on the frontlines of a lead optimization
effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors.
Reactions were performed on âź1 mg scale using glass microvials
providing a miniaturized high-throughput experimentation capability
that was used to study a challenging S<sub><i>N</i></sub>Ar reaction. The availability of robust synthetic chemistry conditions
discovered in these miniaturized investigations enabled the development
of structureâactivity relationships that ultimately led to
the discovery of soluble, selective, and potent inhibitors of DGAT1
Discovery of a 3â(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
Leucine-rich repeat
kinase 2 (LRRK2) is a large, multidomain protein
which contains a kinase domain and GTPase domain among other regions.
Individuals possessing gain of function mutations in the kinase domain
such as the most prevalent G2019S mutation have been associated with
an increased risk for the development of Parkinsonâs disease
(PD). Given this genetic validation for inhibition of LRRK2 kinase
activity as a potential means of affecting disease progression, our
team set out to develop LRRK2 inhibitors to test this hypothesis.
A high throughput screen of our compound collection afforded a number
of promising indazole leads which were truncated in order to identify
a minimum pharmacophore. Further optimization of these indazoles led
to the development of MLi-2 (<b>1</b>): a potent, highly selective,
orally available, brain-penetrant inhibitor of LRRK2