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A Concise Approach to Paxilline Indole Diterpenes
A synthetic
approach to paxilline indole diterpenes is described.
The route to the pentaÂcyclic core relies on a new regioÂselective
alkenylÂation of ketones and a tandem radical addition–aldol
reaction sequence to access vicinal quaternary stereoÂcenters.
Emindole SB, the simplest member of the family, is synthesized in
11 steps from commercially available material to demonstrate the application
of this approach
Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)
We report the discovery and medicinal
chemistry optimization of
a novel series of pyrazole-based inhibitors of human lactate dehydrogenase
(LDH). Utilization of a quantitative high-throughput screening paradigm
facilitated hit identification, while structure-based design and multiparameter
optimization enabled the development of compounds with potent enzymatic
and cell-based inhibition of LDH enzymatic activity. Lead compounds
such as <b>63</b> exhibit low nM inhibition of both LDHA and
LDHB, submicromolar inhibition of lactate production, and inhibition
of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells.
Moreover, robust target engagement of LDHA by lead compounds was demonstrated
using the cellular thermal shift assay (CETSA), and drug–target
residence time was determined via SPR. Analysis of these data suggests
that drug–target residence time (off-rate) may be an important
attribute to consider for obtaining potent cell-based inhibition of
this cancer metabolism target
Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)
We report the discovery and medicinal
chemistry optimization of
a novel series of pyrazole-based inhibitors of human lactate dehydrogenase
(LDH). Utilization of a quantitative high-throughput screening paradigm
facilitated hit identification, while structure-based design and multiparameter
optimization enabled the development of compounds with potent enzymatic
and cell-based inhibition of LDH enzymatic activity. Lead compounds
such as <b>63</b> exhibit low nM inhibition of both LDHA and
LDHB, submicromolar inhibition of lactate production, and inhibition
of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells.
Moreover, robust target engagement of LDHA by lead compounds was demonstrated
using the cellular thermal shift assay (CETSA), and drug–target
residence time was determined via SPR. Analysis of these data suggests
that drug–target residence time (off-rate) may be an important
attribute to consider for obtaining potent cell-based inhibition of
this cancer metabolism target