16 research outputs found
Advances in the synthesis of functionalised pyrrolotetrathiafulvalenes
The electron-donor and unique redox properties of the tetrathiafulvalene (TTF, 1) moiety have led to diverse applications in many areas of chemistry. Monopyrrolotetrathiafulvalenes (MPTTFs, 4) and bispyrrolotetrathiafulvalenes (BPTTFs, 5) are useful structural motifs and have found widespread use in fields such as supramolecular chemistry and molecular electronics. Protocols enabling the synthesis of functionalised MPTTFs and BPTTFs are therefore of broad interest. Herein, we present the synthesis of a range of functionalised MPTTF and BPTTF species. Firstly, the large-scale preparation of the precursor species N-tosyl-(1,3)-dithiolo[4,5-c]pyrrole-2-one (6) is described, as well as the synthesis of the analogue N-tosyl-4,6-dimethyl-(1,3)-dithiolo[4,5-c]pyrrole-2-one (7). Thereafter, we show how 6 and 7 can be used to prepare BPTTFs using homocoupling reactions and functionalised MPTTFs using cross-coupling reactions with a variety of 1,3-dithiole-2-thiones (19). Subsequently, the incorporation of more complex functionality is discussed. We show how the 2-cyanoethyl protecting group can be used to afford MPTTFs functionalised with thioethers, exemplified by a series of ethylene glycol derivatives. Additionally, the merits of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an alternative to the most common deprotecting agent, CsOH·H2O are discussed. Finally, we show how a copper-mediated Ullman-type reaction can be applied to the N-arylation of MPTTFs and BPTTFs using a variety of aryl halides
Affinity-Guided Conjugation to Antibodies for Use in Positron Emission Tomography
The radionuclide
copper-64 is widely used in combination with biomolecules,
such as antibodies, for positron emission tomography (PET). Copper-64
is ideal for the imaging of biomolecules with long circulation times
due to its relatively long half-life, and when conjugated to an antibody,
specific cells can be targeted in vivo. Here, we
have prepared a trastuzumab–chelator conjugate by using affinity-guided
conjugation, in which an azide was attached to the antibody prior
to a strain promoted azide–alkyne cycloaddition reaction with
DBCO-PEG4-NOTA. The conjugate was benchmarked against a
standard nonspecific labeled trastuzumab–NOTA conjugate. The
conjugates were tested for incorporation of copper-64, stability in
buffer and plasma, and tumor targeting in vivo using
PET imaging of mice with xenograft tumors expressing HER2. Both conjugates
showed good incorporation of copper-64 and a high stability with less
than 10% degradation after 36 h. Furthermore, both conjugates showed
accumulation at the tumor site with mean uptake of 7.2 ± 2.4%ID/g
and 5.2 ± 1.3%ID/g after 40 h for the affinity-guided labeled
trastuzumab and the nonspecific labeled trastuzumab, respectively
Oxime Coupling of Active Site Inhibited Factor Seven with a Nonvolatile, Water-Soluble Fluorine-18 Labeled Aldehyde
A nonvolatile fluorine-18
aldehyde prosthetic group was developed
from [18F]SFB, and used for site-specific labeling of active
site inhibited factor VII (FVIIai). FVIIai has a high affinity for
tissue factor (TF), a transmembrane protein involved in angiogenesis,
proliferation, cell migration, and survival of cancer cells. A hydroxylamine
N-glycan modified FVIIai (FVIIai-ONH2) was used for oxime
coupling with the aldehyde [18F]2 under mild
and optimized conditions in an isolated RCY of 4.7 ± 0.9%, and
a synthesis time of 267 ± 5 min (from EOB). Retained binding
and specificity of the resulting [18F]FVIIai to TF was
shown in vitro. TF-expression imaging capability was evaluated by
in vivo PET/CT imaging in a pancreatic human xenograft cancer mouse
model. The conjugate showed exceptional stability in plasma (>95%
at 4 h) and a binding fraction of 90%. In vivo PET/CT imaging showed
a mean tumor uptake of 3.8 ± 0.2% ID/g at 4 h post-injection,
a comparable uptake in liver and kidneys, and low uptake in normal
tissues. In conclusion, FVIIai was labeled with fluorine-18 at the
N-glycan chain without affecting TF binding. In vitro specificity
and a good in vivo imaging contrast at 4 h postinjection was
demonstrated