3 research outputs found
Electrophile-Integrating Smiles Rearrangement Provides Previously Inaccessible C4′‑<i>O</i>‑Alkyl Heptamethine Cyanine Fluorophores
New synthetic methods to rapidly
access useful fluorophores are
needed to advance modern molecular imaging techniques. A new variant
of the classical Smiles rearrangement is reported that enables the
efficient synthesis of previously inaccessible C4′-<i>O-</i>alkyl heptamethine cyanines. The key reaction involves <i>N</i>- to <i>O</i>- transposition with selective electrophile
incorporation on nitrogen. A representative fluorophore exhibits excellent
resistance to thiol nucleophiles, undergoes productive bioconjugation,
and can be used in near-IR fluorescence imaging applications
Synthesis of Hindered Anilines: Three-Component Coupling of Arylboronic Acids, <i>tert</i>-Butyl Nitrite, and Alkyl Bromides
The
synthesis of sterically hindered amines has been a significant
challenge in organic chemistry. Herein, we report a modular, three-component
coupling that constructs two carbon–nitrogen bonds including
a sterically hindered C<sub>sp</sub><sup>3</sup>–N bond using
commercially available materials. This process uses an earth-abundant
copper catalyst and mild reaction conditions, allowing access to a
variety of complex aromatic amines
Impact of C4′‑<i>O</i>‑Alkyl Linker on <i>in Vivo</i> Pharmacokinetics of Near-Infrared Cyanine/Monoclonal Antibody Conjugates
Near-infrared (NIR) fluorophores
have several advantages over visible-light
fluorophores, including superior tissue penetration and lower autofluorescence.
We recently accessed a new class of readily synthesized NIR cyanines
containing a novel C4′-<i>O</i>-alkyl linker, which
provides both high chemical stability and excellent optical properties.
In this study, we provide the first <i>in vivo</i> analysis
of this new class of compounds, represented by the tetrasulfonate
FNIR-774 (Frederick NIR 774). Monoclonal antibody (mAb) conjugates
of FNIR-774 were compared to conjugates of the commercially available
dye (IRDye800CW (IR800)), one of the most widely used NIR fluorophores
for clinical translation. Both dyes were conjugated to panitumumab
(pan) or cetuximab (cet) with ratios of 1:2 or 1:5. Conjugates of
both dyes demonstrated similar quenching capacity, stability, and
brightness in target cells <i>in vitro</i>. In contrast, <i>in vivo</i> imaging in mice showed different pharmacokinetics
between pan-FNIR-774 (1:5) and pan-IR800 (1:5), or cet-FNIR-774 (1:5)
and cet-IR800 (1:5). Particularly at the higher labeling density,
mAb-FNIR-774 conjugates showed superior specific accumulation in tumors
compared with mAb-IR800 conjugates. Thus, FNIR-774 conjugates showed
superior <i>in vivo</i> pharmacokinetics compared with IR800
conjugates, independent of the mAb. These results suggest that FNIR-774
is a promising fluorescent probe for NIR optical imaging