5 research outputs found
Synthesis of 6,6′-Binaphthopyran-2-one Natural Products: Pigmentosin A, Talaroderxines A and B
Efficient and stereoselective syntheses of pigmentosin A, talaroderxine A, and its diastereomer talaroderxine B are reported. The binaphthyl ring system is assembled by vanadium-catalyzed phenolic coupling of tricyclic precursors. These key intermediates were prepared by Michael–Dieckmann annulation of a protected orsellinate ester, with the requisite pyranones accessed by a new variant of Ghosez’s sulfone-epoxide annulation. Preliminary biological experiments are reported for pigmentosin
Comparison of Small Molecule Inhibitors of the Bacterial Cell Division Protein FtsZ and Identification of a Reliable Cross-Species Inhibitor
FtsZ is a guanosine triphosphatase (GTPase) that mediates
cytokinesis
in bacteria. FtsZ is homologous in structure to eukaryotic tubulin
and polymerizes in a similar head-to-tail fashion. The study of tubulin’s
function in eukaryotic cells has benefited greatly from specific and
potent small molecule inhibitors, including colchicine and taxol.
Although many small molecule inhibitors of FtsZ have been reported,
none has emerged as a generally useful probe for modulating bacterial
cell division. With the goal of establishing a useful and reliable
small molecule inhibitor of FtsZ, a broad biochemical cross-comparison
of reported FtsZ inhibitors was undertaken. Several of these molecules,
including phenolic natural products, are unselective inhibitors that
seem to derive their activity from the formation of microscopic colloids
or aggregates. Other compounds, including the natural product viriditoxin
and the drug development candidate PC190723, exhibit no inhibition
of GTPase activity using protocols in this work or under published
conditions. Of the compounds studied, only zantrin Z3 exhibits good
levels of inhibition, maintains activity under conditions that disrupt
small molecule aggregates, and provides a platform for exploration
of structure–activity relationships (SAR). Preliminary SAR
studies have identified slight modifications to the two side chains
of this structure that modulate the inhibitory activity of zantrin
Z3. Collectively, these studies will help focus future investigations
toward the establishment of probes for FtsZ that fill the roles of
colchicine and taxol in studies of tubulin
Discovery of <i>N</i>‑Alkyl Piperazine Side Chain Based CXCR4 Antagonists with Improved Drug-like Properties
A novel
series of CXCR4 antagonists with piperidinyl and piperazinyl
alkylamine side chains designed as butyl amine replacements are described.
Several of these compounds showed similar activity to the parent compound
TIQ-15 (<b>5</b>) in a SDF-1 induced calcium flux assay. Preliminary
structure–activity relationship investigations led us to identify
a series containing <i>N</i>-propyl piperazine side chain
analogs exemplified by <b>16</b> with improved off-target effects
as measured in a muscarinic acetylcholine receptor (mAChR) calcium
flux assay and in a limited drug safety panel screen. Further efforts
to explore SAR and optimize drug properties led to the identification
of the <i>N</i>′-ethyl-<i>N</i>-propyl-piperazine
tetrahydroisoquinoline derivative <b>44</b> and the <i>N</i>-propyl-piperazine benzimidazole compound <b>37</b>, which gave the best overall profiles with no mAChR or CYP450 inhibition,
good permeability in PAMPA assays, and metabolic stability in human
liver microsomes
Synthesis of Novel Tetrahydroisoquinoline CXCR4 Antagonists with Rigidified Side-Chains
A structure–activity
relationship study of potent TIQ15-derived
CXCR4 antagonists is reported. In this investigation, the TIQ15 side-chain
was constrained to improve its drug properties. The cyclohexylamino
congener <b>15a</b> was found to be a potent CXCR4 inhibitor
(IC<sub>50</sub> = 33 nM in CXCL12-mediated Ca<sup>2+</sup> flux)
with enhanced stability in liver microsomes and reduced inhibition
of CYP450 (2D6). The improved CXCR4 antagonist <b>15a</b> has
potential therapeutic application as a single agent or combinatory
anticancer therapy
Discovery of Tetrahydroisoquinoline-Containing CXCR4 Antagonists with Improved in Vitro ADMET Properties
CXCR4 is a seven-transmembrane
receptor expressed by hematopoietic
stem cells and progeny, as well as by ≥48 different cancers
types. CXCL12, the only chemokine ligand of CXCR4, is secreted within
the tumor microenvironment, providing sanctuary for CXCR4<sup>+</sup> tumor cells from immune surveillance and chemotherapeutic elimination
by (1) stimulating prosurvival signaling and (2) recruiting CXCR4<sup>+</sup> immunosuppressive leukocytes. Additionally, distant CXCL12-rich
niches attract and support CXCR4<sup>+</sup> metastatic growths. Accordingly,
CXCR4 antagonists can potentially obstruct CXCR4-mediated prosurvival
signaling, recondition the CXCR4<sup>+</sup> leukocyte infiltrate
from immunosuppressive to immunoreactive, and inhibit CXCR4<sup>+</sup> cancer cell metastasis. Current small molecule CXCR4 antagonists
suffer from poor oral bioavailability and off-target liabilities.
Herein, we report a series of novel tetrahydroÂisoquinoline-containing
CXCR4 antagonists designed to improve intestinal absorption and off-target
profiles. Structure–activity relationships regarding CXCR4
potency, intestinal permeability, metabolic stability, and cytochrome
P450 inhibition are presented