7 research outputs found
Total Syntheses of (−)-Pyrimidoblamic Acid and P‑3A
Total
syntheses of (<b>−</b>)-pyrimidoblamic acid
and P-3A are disclosed. Central to the convergent approach is a powerful
inverse electron demand Diels–Alder reaction between substituted
electron-deficient 1,2,3-triazines and a highly functionalized and
chiral primary amidine, which forms the pyrimidine cores and introduces
all necessary stereochemistry in a single step. Intrinsic in the convergent
approach is the potential it provides for the late stage divergent
synthesis of modified analogs bearing deep-seated changes in either
the pyrimidine cores or the highly functionalized C2 side chain common
to both natural products. The examination of the key cycloaddition
reaction revealed that the inherent 1,2,3-triazine mode of cycloaddition
(C4/N1 vs C5/N2) as well as the amidine regioselectivity were unaffected
by introduction of two electron-withdrawing groups (−CO<sub>2</sub>R) at C4 and C6 of the 1,2,3-triazine even if C5 is unsubstituted
(Me or H), highlighting the synthetic potential of the powerful pyrimidine
synthesis
Sclerotiamide: The First Non-Peptide-Based Natural Product Activator of Bacterial Caseinolytic Protease P
Caseinolytic protease P (ClpP) maintains
essential roles in bacterial
homeostasis. As such, both the inhibition and activation of this enzyme
result in bactericidal activity, making ClpP a promising target for
antibacterial drug development. Herein, we report the results of a
fluorescence-based screen of ∼450 structurally diverse fungal
and bacterial secondary metabolites. Sclerotiamide (<b>1</b>), a paraherquamide-related indolinone, was identified as the first
non-peptide-based natural product activator of ClpP. Structure-activity
relationships arising from the initial screen, preliminary biochemical
evaluation of <b>1</b>, and rationale for the exploitation of
this chemotype to develop novel ClpP activators are presented
Cycloadditions of Noncomplementary Substituted 1,2,3-Triazines
The scope of the [4 + 2] cycloaddition
reactions of substituted
1,2,3-triazines, bearing noncomplementary substitution with electron-withdrawing
groups at C4 and/or C6, is described. The studies define key electronic
and steric effects of substituents impacting the reactivity, mode
(C4/N1 vs C5/N2), and regioselectivity of the cycloaddition reactions
of 1,2,3-triazines with amidines, enamines, and ynamines, providing
access to highly functionalized heterocycles
A Fundamental Relationship between Hydrophobic Properties and Biological Activity for the Duocarmycin Class of DNA-Alkylating Antitumor Drugs: Hydrophobic-Binding-Driven Bonding
Two systematic series of increasingly
hydrophilic derivatives of
duocarmycin SA that feature the incorporation of ethylene glycol units
(<i>n</i> = 1–5) into the methoxy substituents of
the trimethoxyindole subunit are described. These derivatives exhibit
progressively increasing water solubility along with progressive decreases
in cell growth inhibitory activity and DNA alkylation efficiency with
the incremental ethylene glycol unit incorporations. Linear relationships
of cLogP with −log IC<sub>50</sub> for cell growth inhibition
and −log AE (AE = cell-free DNA alkylation efficiency)
were observed, with the cLogP values spanning the productive range
of 2.5–0.49 and the −log IC<sub>50</sub> values
spanning the range of 11.2–6.4, representing IC<sub>50</sub> values that vary by a factor of 10<sup>5</sup> (0.008 to 370 nM).
The results quantify the fundamental role played by the hydrophobic
character of the compound in the expression of the biological activity
of members in this class (driving the intrinsically reversible DNA
alkylation reaction) and define the stunning magnitude of its effect
Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding
Grp94 and Hsp90, the ER and cytoplasmic
hsp90 paralogs, share a
conserved ATP-binding pocket that has been targeted for therapeutics.
Paralog-selective inhibitors may lead to drugs with fewer side effects.
Here, we analyzed <b>1</b> (BnIm), a benzyl imidazole resorcinylic
inhibitor, for its mode of binding. The structures of <b>1</b> bound to Hsp90 and Grp94 reveal large conformational changes in
Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent
to the central ATP cavity that is ordinarily blocked. The Grp94:<b>1</b> structure reveals a flipped pose of the resorcinylic scaffold
that inserts into the exposed site 2. We exploited this flipped binding
pose to develop a Grp94-selective derivative of <b>1</b>. Our
structural analysis shows that the ability of the ligand to insert
its benzyl imidazole substituent into site 1, a different side pocket
off the ATP binding cavity, is the key to exposing site 2 in Grp94
Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding
Grp94 and Hsp90, the ER and cytoplasmic
hsp90 paralogs, share a
conserved ATP-binding pocket that has been targeted for therapeutics.
Paralog-selective inhibitors may lead to drugs with fewer side effects.
Here, we analyzed <b>1</b> (BnIm), a benzyl imidazole resorcinylic
inhibitor, for its mode of binding. The structures of <b>1</b> bound to Hsp90 and Grp94 reveal large conformational changes in
Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent
to the central ATP cavity that is ordinarily blocked. The Grp94:<b>1</b> structure reveals a flipped pose of the resorcinylic scaffold
that inserts into the exposed site 2. We exploited this flipped binding
pose to develop a Grp94-selective derivative of <b>1</b>. Our
structural analysis shows that the ability of the ligand to insert
its benzyl imidazole substituent into site 1, a different side pocket
off the ATP binding cavity, is the key to exposing site 2 in Grp94
Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides
The acyldepsipeptide
(ADEP) antibiotics operate through a clinically
unexploited mechanism of action and thus have attracted attention
from several antibacterial development groups. The ADEP scaffold is
synthetically tractable, and deep-seated modifications have produced
extremely potent antibacterial leads against Gram-positive pathogens.
Although newly identified ADEP analogs demonstrate remarkable antibacterial
activity against bacterial isolates and in mouse models of bacterial
infections, stability issues pertaining to the depsipeptide core remain.
To date, no study has been reported on the natural ADEP scaffold that
evaluates the sole importance of the macrocyclic linkage on target
engagement, molecular conformation, and bioactivity. To address this
gap in ADEP structure–activity relationships, we synthesized
three ADEP analogs that only differ in the linkage motif (i.e., ester,
amide, and <i>N</i>-methyl amide) and provide a side-by-side
comparison of conformational behavior and biological activity. We
demonstrate that while replacement of the naturally occurring ester
linkage with a secondary amide maintains <i>in vitro</i> biochemical activity, this simple substitution results in a significant
drop in whole-cell activity. This study provides direct evidence that
ester to amide linkage substitution is unlikely to provide a reasonable
solution for ADEP instability