6 research outputs found
Crystal structure and solid state computational (DFT/Hirshfeld surface) study for probing a new efficient and recyclable oxidation reagent, 1,2-ethandiylbis(triphenylphosphonium) peroxodisulfate dihydrate
<p>A new, efficient and recyclable reagent, 1,2-Ethandiylbis(triphenylphosphonium) peroxodisulfate dihydrate, for the oxidation of benzylic alcohols has been synthesized and characterized by IR, NMR spectroscopy, and single crystal X-ray crystallography. Using the title compound, the results indicate that the oxidation reactions are rapid, take place under mild reaction conditions, easily to work-up and high yielding. The Hirshfeld surface and associated finger print plots were derived from the X-ray structure to visualize the significant nonclassical C-H â‹…â‹…â‹… O/Ď€ interactions in the crystal packing. The geometry, vibrational spectroscopy and electronic properties of the bis(triphenylphosphonium) dication have also been investigated by various DFT computational methods.</p
Investigation into the Biological Impact of Block Size on Cathepsin S‑Degradable HPMA Copolymers
<i>N</i>-(2-Hydroxypropyl)Âmethacrylamide (HPMA) copolymers
have been studied as an efficient carrier for drug delivery and tumor
imaging. However, as with many macromolecular platforms, the substantial
accumulation of HPMA copolymer by the mononuclear phagocyte system
(MPS)-associated tissues, such as the blood, liver, and spleen, has
inhibited its clinical translation. Our laboratory is pursuing approaches
to improve the diagnostic and radiotherapeutic effectiveness of HPMA
copolymers by reducing the nontarget accumulation. Specifically, we
have been investigating the use of a cathepsin S (Cat S)-cleavable
peptidic linkers to degrade multiblock HPMA copolymers to increase
MPS-associated tissue clearance. In this study, we further our investigation
into this area by exploring the impact of copolymer block size on
the biological performance of Cat S-degradable HPMA copolymers. Using
a variety of <i>in vitro</i> and <i>in vivo</i> techniques, including dual labeling of the copolymer and peptide
components, we investigated the constructs using HPAC pancreatic ductal
adenocarcinoma models. The smaller copolymer block size (S-CMP) demonstrated
significantly faster Cat S cleavage kinetics relative to the larger
system (L-CMP). Confocal microscopy demonstrated that both constructs
could be much more efficiently internalized by human monocyte-differentiated
macrophage (hMDM) compared to HPAC cells. In the biodistribution studies,
the multiblock copolymers with a smaller block size exhibited faster
clearance and lower nontarget retention while still achieving good
tumor targeting and retention. Based on the radioisotopic ratios,
fragmentation and clearance of the copolymer constructs were higher
in the liver compared to the spleen and tumor. Overall, these results
indicate that block size plays an important role in the biological
performance of Cat S-degradable polymeric constructs
Development of Hypoxia Enhanced <sup>111</sup>In-Labeled Bombesin Conjugates: Design, Synthesis, and In Vitro Evaluation in PC-3 Human Prostate Cancer
The gastrin-releasing peptide receptor (BB2r) has shown
great promise
for tumor targeting due to the increase of the receptor expression
in a variety of human cancers including prostate, breast, small-cell
lung, and pancreatic cancer. From clinical investigations, prostate
cancer has been shown to be among the most hypoxic of the cancers
investigated. Many solid tumors contain regions of hypoxia due to
poor organization and efficiency of the vasculature. However, hypoxia
is typically not present in normal tissue. Nitroimidazoles, a thoroughly
investigated class of hypoxia selective drugs, have been shown to
be highly retained in hypoxic tissues. The purpose of this study is
to determine if the incorporation of hypoxia trapping moieties into
the structural paradigm of BB2r-targeted peptides will increase the
retention time of the agents in prostate cancer tumors. The present
work involves the design, syntheses, purification, and in vitro investigation
of hypoxia enhanced <sup>111</sup>In-BB2r-targeted radioconjugates.
A total of four BB2r-targeted conjugates (<b>1</b>–<b>4</b>) were synthesized and coupled with increasing numbers of
2-nitroimidazoles, a hypoxia trapping moiety. Conjugates were radiolabeled
with <sup>111</sup>In and purified by HPLC prior to in vitro studies.
Receptor saturation assays under both normoxic and hypoxic conditions
showed that the BB2r receptor expression on the PC-3 human prostate
cancer cell line was not significantly affected by oxygen levels.
Competitive binding assays revealed that incorporation of 2-nitroimidazoles
had a detrimental effect to BB2r binding when adequate spacer groups,
between the hypoxia trapping agent and the pharmacophore, were not
employed. All of the 2-nitroimidazole containing BB2r-targeted agents
exhibited significantly higher longitudinal retention in PC-3 cells
under hypoxic conditions compared to the analogous normoxic studies.
Protein association analysis revealed a 3-fold increase in binding
of a 2-nitroimidazole containing BB2r-targeted agent under hypoxic
relative to normoxic conditions. The positive nature of these results
indicate that further exploration into the potential of hypoxia selective
trapping agents for BB2r-targeted agents, as well as other targeted
compounds, is warranted
Formation of 2‑Imino Benzo[<i>e</i>]‑1,3-oxazin-4-ones from Reactions of Salicylic Acids and Anilines with HATU: Mechanistic and Synthetic Studies
We
describe a new 1-[BisÂ(dimethylamino)Âmethylene]-1<i>H</i>-1,2,3-triazoloÂ[4,5-<i>b</i>]Âpyridinium 3-oxide hexafluorophosphate
(HATU)-mediated coupling reaction to produce 2-imino benzoÂ[<i>e</i>]-1,3-oxazin-4-ones from salicylic acids and anilines.
Mechanistic studies support a reaction pathway in which HATU mediates
carbon transfer to the initially formed salicylanilides to form in
succession reactive tetramethylisouronium and <i>N</i>-acylÂ(dimethyl)Âisouronium
intermediates, which then undergo imine–iminium exchange to
generate the desired oxazinones
Structure–Activity Relationship Studies with Tetrahydroquinoline Analogs as EPAC Inhibitors
EPAC proteins are
therapeutic targets for the potential treatment
of cardiac hypertrophy and cancer metastasis. Several laboratories
use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1
in various disease states. Here, we report SAR studies with tetrahydroquinoline
analogs that explore various functional groups. The most potent EPAC
inhibitor <b>12a</b> exists as a mixture of inseparable <i>E</i> (major) and <i>Z</i> (minor) rotamers. The rotation
about the <i>N</i>-formyl group indeed impacts the activity
against EPAC
Structure–Activity Relationship Studies with Tetrahydroquinoline Analogs as EPAC Inhibitors
EPAC proteins are
therapeutic targets for the potential treatment
of cardiac hypertrophy and cancer metastasis. Several laboratories
use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1
in various disease states. Here, we report SAR studies with tetrahydroquinoline
analogs that explore various functional groups. The most potent EPAC
inhibitor <b>12a</b> exists as a mixture of inseparable <i>E</i> (major) and <i>Z</i> (minor) rotamers. The rotation
about the <i>N</i>-formyl group indeed impacts the activity
against EPAC