7 research outputs found
Continuous Multiple Liquid–Liquid Separation: Diazotization of Amino Acids in Flow
A second-generation laboratory-scale, modular liquid–liquid separation device based on computer-controlled high-pressure pumps and a high-resolution digital camera has been invented. The diazotization of amino acids to produce valuable chiral hydroxyacids is demonstrated in flow for the first time. The use of a triple-separator system in conjuction with the developed diazotization process allows the safe and efficient production and automated isolation of multigram quantities of valuable chiral hydroxyacids
Continuous Multiple Liquid–Liquid Separation: Diazotization of Amino Acids in Flow
A second-generation laboratory-scale, modular liquid–liquid separation device based on computer-controlled high-pressure pumps and a high-resolution digital camera has been invented. The diazotization of amino acids to produce valuable chiral hydroxyacids is demonstrated in flow for the first time. The use of a triple-separator system in conjuction with the developed diazotization process allows the safe and efficient production and automated isolation of multigram quantities of valuable chiral hydroxyacids
Catalytic Enantioselective Dihalogenation and the Selective Synthesis of (−)-Deschloromytilipin A and (−)-Danicalipin A
A titanium-based catalytic enantioselective
dichlorination of simple
allylic alcohols is described. This dichlorination reaction provides
stereoselective access to all common dichloroalcohol building blocks
used in syntheses of chlorosulfolipid natural products. An enantioselective
synthesis of <i>ent</i>-(−)-deschloromytilipin A
and a concise, eight-step synthesis of <i>ent</i>-(−)-danicalipin
A are executed and employ the dichlorination reaction as the first
step. Extension of this system to enantioselective dibromination and
its use in the synthesis of pentabromide stereoarrays relevant to
bromosulfolipids is reported. The described dichlorination and dibromination
reactions are capable of exerting diastereocontrol in complex settings
allowing X-ray crystal structure analysis of natural and unnatural
diastereomers of polyhalogenated stereohexads
Elimination of Butylcycloheptylprodigiosin as a Known Natural Product Inspired by an Evolutionary Hypothesis for Cyclic Prodigiosin Biosynthesis
The cyclic prodigiosins are an important
family of bioactive natural
products that continue to be the subject of numerous structural, synthetic,
and biosynthetic studies. In particular, the structural assignments
of the isomeric cyclic prodigiosins butylcycloheptylprodigiosin (BCHP)
and streptorubin B have been the cause of significant confusion. Herein,
we report detailed studies regarding the electron impact (EI) mass
spectra of synthetic BCHP and streptorubin B that have allowed us
to distinguish the two compounds in the absence of quality historical
isolation NMR data. On the basis of these fragmentation differences,
the status of BCHP as a natural product is challenged. The proposed
mechanism of fragmentation is supported by the EI mass spectra of
synthetic pentyl-chain analogues of BCHP and streptorubin B, X-ray
crystallography, and DFT calculations. Elimination of BCHP from the
prodigiosin family supports a proposed evolutionary hypothesis for
the surprising biosynthesis of cyclic prodigiosins
Elimination of Butylcycloheptylprodigiosin as a Known Natural Product Inspired by an Evolutionary Hypothesis for Cyclic Prodigiosin Biosynthesis
The cyclic prodigiosins are an important
family of bioactive natural
products that continue to be the subject of numerous structural, synthetic,
and biosynthetic studies. In particular, the structural assignments
of the isomeric cyclic prodigiosins butylcycloheptylprodigiosin (BCHP)
and streptorubin B have been the cause of significant confusion. Herein,
we report detailed studies regarding the electron impact (EI) mass
spectra of synthetic BCHP and streptorubin B that have allowed us
to distinguish the two compounds in the absence of quality historical
isolation NMR data. On the basis of these fragmentation differences,
the status of BCHP as a natural product is challenged. The proposed
mechanism of fragmentation is supported by the EI mass spectra of
synthetic pentyl-chain analogues of BCHP and streptorubin B, X-ray
crystallography, and DFT calculations. Elimination of BCHP from the
prodigiosin family supports a proposed evolutionary hypothesis for
the surprising biosynthesis of cyclic prodigiosins
Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
General
control nonderepressible 2 (GCN2) protein kinase is a cellular
stress sensor within the tumor microenvironment (TME), whose signaling
cascade has been proposed to contribute to immune escape in tumors.
Herein, we report the discovery of cell-potent GCN2 inhibitors with
excellent selectivity against its closely related Integrated Stress
Response (ISR) family members heme-regulated inhibitor kinase (HRI),
protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase
(PERK), as well as good kinome-wide selectivity and favorable PK.
In mice, compound 39 engages GCN2 at levels ≥80%
with an oral dose of 15 mg/kg BID. We also demonstrate the ability
of compound 39 to alleviate MDSC-related T cell suppression
and restore T cell proliferation, similar to the effect seen in MDSCs
from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI)
as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced
by treatment with compound 39 demonstrating the complementarity
of these two mechanisms
Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
General
control nonderepressible 2 (GCN2) protein kinase is a cellular
stress sensor within the tumor microenvironment (TME), whose signaling
cascade has been proposed to contribute to immune escape in tumors.
Herein, we report the discovery of cell-potent GCN2 inhibitors with
excellent selectivity against its closely related Integrated Stress
Response (ISR) family members heme-regulated inhibitor kinase (HRI),
protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase
(PERK), as well as good kinome-wide selectivity and favorable PK.
In mice, compound 39 engages GCN2 at levels ≥80%
with an oral dose of 15 mg/kg BID. We also demonstrate the ability
of compound 39 to alleviate MDSC-related T cell suppression
and restore T cell proliferation, similar to the effect seen in MDSCs
from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI)
as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced
by treatment with compound 39 demonstrating the complementarity
of these two mechanisms