29 research outputs found
Emulating the Logic of Monoterpenoid Alkaloid Biogenesis to Access a Skeletally Diverse Chemical Library
We
have developed a synthetic strategy that mimics the diversity-generating
power of monoterpenoid indole alkaloid biosynthesis. Our general approach
goes beyond diversification of a single natural product-like substructure
and enables production of a highly diverse collection of small molecules.
The reaction sequence begins with rapid and highly modular assembly
of the tetracyclic indoloquinolizidine core, which can be chemoselectively
processed into several additional skeletally diverse structural frameworks.
The general utility of this approach was demonstrated by parallel
synthesis of two representative chemical libraries containing 847
compounds with favorable physicochemical properties to enable its
subsequent broad pharmacological evaluation
Emulating the Logic of Monoterpenoid Alkaloid Biogenesis to Access a Skeletally Diverse Chemical Library
We
have developed a synthetic strategy that mimics the diversity-generating
power of monoterpenoid indole alkaloid biosynthesis. Our general approach
goes beyond diversification of a single natural product-like substructure
and enables production of a highly diverse collection of small molecules.
The reaction sequence begins with rapid and highly modular assembly
of the tetracyclic indoloquinolizidine core, which can be chemoselectively
processed into several additional skeletally diverse structural frameworks.
The general utility of this approach was demonstrated by parallel
synthesis of two representative chemical libraries containing 847
compounds with favorable physicochemical properties to enable its
subsequent broad pharmacological evaluation
Identification of Fumarate Hydratase Inhibitors with Nutrient-Dependent Cytotoxicity
Development
of cell-permeable small molecules that target enzymes
involved in energy metabolism remains important yet challenging. We
describe here the discovery of a new class of compounds with a nutrient-dependent
cytotoxicity profile that arises from pharmacological inhibition of
fumarate hydratase (also known as fumarase). This finding was enabled
by a high-throughput screen of a diverse chemical library in a panel
of human cancer cell lines cultured under different growth conditions,
followed by subsequent structure–activity optimization and
target identification. While the highest cytotoxicity was observed
under low glucose concentrations, the antiproliferative activities
and inhibition of oxygen consumption rates in cells were distinctly
different from those displayed by typical inhibitors of mitochondrial
oxidative phosphorylation. The use of a photoaffinity labeling strategy
identified fumarate hydratase as the principal pharmacological target.
Final biochemical studies confirmed dose-dependent, competitive inhibition
of this enzyme <i>in vitro</i>, which was fully consistent
with the initially observed growth inhibitory activity. Our work demonstrates
how the phenotypic observations combined with a successful target
identification strategy can yield a useful class of pharmacological
inhibitors of an enzyme involved in the operation of tricarboxylic
acid cycle