2 research outputs found
Wilcox Molecular Torsion Balance with Rigid Side Arm and Separable Atropisomers for Investigating CH−π Interactions
A new
variant of the Wilcox molecular torsion balance featuring a naphthyl-alkyl
side arm was synthesized. The energy barrier for axial isomerization
in the new balance was sufficiently high to allow for separation of
the two rotamers and to observe their isomerization kinetics. The
CH−π interaction energies in derivatives of the new and
the original ester balance were in close agreement, suggesting that
the motion in ester linkage is not an important factor in folding
in the ester balance
<i>In Vitro</i> Optimization of EtNBS-PDT against Hypoxic Tumor Environments with a Tiered, High-Content, 3D Model Optical Screening Platform
Hypoxia and acidosis are widely recognized as major contributors
to the development of treatment resistant cancer. For patients with
disseminated metastatic lesions, such as most women with ovarian cancer
(OvCa), the progression to treatment resistant disease is almost always
fatal. Numerous therapeutic approaches have been developed to eliminate
treatment resistant carcinoma, including novel biologic, chemo, radiation,
and photodynamic therapy (PDT) regimens. Recently, PDT using the cationic
photosensitizer EtNBS was found to be highly effective against therapeutically
unresponsive hypoxic and acidic OvCa cellular populations <i>in vitro.</i> To optimize this treatment regimen, we developed
a tiered, high-content, image-based screening approach utilizing a
biologically relevant OvCa 3D culture model to investigate a small
library of side-chain modified EtNBS derivatives. The uptake, localization,
and photocytotoxicity of these compounds on both the cellular and
nodular levels were observed to be largely mediated by their respective
ethyl side chain chemical alterations. In particular, EtNBS and its
hydroxyl-terminated derivative (EtNBS-OH) were found to have similar
pharmacological parameters, such as their nodular localization patterns
and uptake kinetics. Interestingly, these two molecules were found
to induce dramatically different therapeutic outcomes: EtNBS was found
to be more effective in killing the hypoxic, nodule core cells with
superior selectivity, while EtNBS-OH was observed to trigger widespread
structural degradation of nodules. This breakdown of the tumor architecture
can improve the therapeutic outcome and is known to synergistically
enhance the antitumor effects of front-line chemotherapeutic regimens.
These results, which would not have been predicted or observed using
traditional monolayer or <i>in vivo</i> animal screening
techniques, demonstrate the powerful capabilities of 3D <i>in
vitro</i> screening approaches for the selection and optimization
of therapeutic agents for the targeted destruction of specific cellular
subpopulations