14 research outputs found
An Ester Enolate–Claisen Rearrangement Route to Substituted 4-Alkylideneprolines. Studies toward a Definitive Structural Revision of Lucentamycin A
Substituted 4-alkylideneprolines represent a rare class
of naturally occurring amino acids with promising biological activities.
Lucentamycin A is a cytotoxic, marine-derived tripeptide that harbors
a 4-ethylidine-3-methylproline (Emp) residue unique among known peptide
natural products. In this paper, we examine the synthesis of Emp and related 4-alkylideneprolines
employing a versatile ester enolate–Claisen rearrangement.
The scope and selectivity of the key rearrangement reaction are described
with a number of diversely substituted glycine ester substrates. Treatment
of the allyl esters with excess NaHMDS at ambient temperature gives
rise to highly substituted α-allylglycine products with good
to excellent diastereoselectivities. Resolution of dipeptide diastereomers
and cyclization to form the pyrrolidine rings provide rapid access
to stereopure prolyl dipeptides. We have applied this strategy to
the synthesis of four Emp-containing isomers of lucentamycin A in
pursuit of a definitive stereochemical revision of the natural product.
Our studies indicate that the Emp stereogenic centers are not the
source of structural misassignment. The current strategy should find
broad utility in the synthesis of additional natural product analogues
and related 3-alkyl-4-alkylidene prolines
Solid-Phase Synthesis of TetraÂhydroÂpyridazineÂdione-Constrained Peptides
The
design and solid-phase synthesis of tetrahydropyridazine-3,6-dione
(Tpd) peptidomimetics derived from backbone-aminated peptides is reported.
The described protocol features the synthesis of chiral α-hydrazino
acids suitable for chemoselective incorporation into growing peptide
chains. Acid-catalyzed cyclization to form the Tpd ring during cleavage
affords the target peptidomimetics in good yield and purity. The scope
of Tpd incorporation is demonstrated through the synthesis of constrained
peptides featuring nucleophilic/electrophilic side chains and sterically
encumbered α-substituted hydrazino acid residues
Total Synthesis and Structural Revision of Lucentamycin A
Lucentamycin A is a marine-derived peptide natural product
harboring
a unique 4-ethylidene-3-methylproline (Emp) subunit. The proposed
structure of lucentamycin A and the core Emp residue have recently
been called into question through synthesis. Here, we report the first
total synthesis of lucentamycin A, which confirms that the ethylidene
substituent in Emp bears an <i>E</i> geometry, in contrast
to the originally assigned <i>Z</i> configuration. Synthesis
of the desired (<i>E</i>)-Emp subunit required the implementation
of a novel strategy starting from Garner’s aldehyde
β-Strand Mimics based on Tetrahydropyridazinedione (tpd) Peptide Stitching
Short peptides featuring a tetrahydropyridazinedione (tpd) backbone tether exhibit reduced conformational flexibility external to the heterocyclic constraint. Analysis by NMR, molecular modeling and X-ray crystallography suggests both covalent and non-covalent stabilization of extended peptide conformations. An efficient solid-phase protocol was developed for the synthesis of a new class of β-strand mimics based on oligomeric tpd subunits
Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells
Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In EÎĽ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3\u273\u27-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3\u273\u27-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells
Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells
Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In EÎĽ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3\u273\u27-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3\u273\u27-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells
Total Synthesis and Structural Revision of Lucentamycin A
Lucentamycin A is a marine-derived peptide natural product
harboring
a unique 4-ethylidene-3-methylproline (Emp) subunit. The proposed
structure of lucentamycin A and the core Emp residue have recently
been called into question through synthesis. Here, we report the first
total synthesis of lucentamycin A, which confirms that the ethylidene
substituent in Emp bears an <i>E</i> geometry, in contrast
to the originally assigned <i>Z</i> configuration. Synthesis
of the desired (<i>E</i>)-Emp subunit required the implementation
of a novel strategy starting from Garner’s aldehyde
Synthesis of Novel Tricyclic Chromenone-Based Inhibitors of IRE‑1 RNase Activity
Inositol-requiring enzyme 1 (IRE-1)
is a kinase/RNase ER stress
sensor that is activated in response to excessive accumulation of
unfolded proteins, hypoxic conditions, calcium imbalance, and other
stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective
effect and has been implicated in the progression of cancer via increased
expression of the transcription factor XBP-1s. Here, we describe the
synthesis and biological evaluation of novel chromenone-based covalent
inhibitors of IRE-1. Preparation of a family of 8-formylÂtetrahydroÂchromenoÂ[3,4-<i>c</i>]Âpyridines was achieved via a Duff formylation that
is attended by an unusual cyclization reaction. Biological evaluation
in vitro and in whole cells led to the identification of <b>30</b> as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression
in wild type B cells and human mantle cell lymphoma cell lines