Chemistry Reference
In-Depth Information
biological processes. This strategy was recently disclosed by Carlson and colleagues
(2007), who used an RGD peptidomimetic to bind to a
n
b
3
integrins, which enabled
the a-Gal epitope that was tethered to the peptidomimetic to form a multifunctional
display for binding to anti-a-galactosyl antibodies on cells with high integrin levels.
Alternatively, Baker's group (Majoros et al. 2006) synthesized multifunctionalized
dendrimers with a random distribution of functional groups simply by controlling the
number of equivalents of each terminal group that were added, and linear polymers
with a random distribution of mannose and galactose were studied (Cairo et al. 2002;
Majoros et al. 2006). Similar to Baker's method, we used controlled equivalents of
isothiocyanato sugars to create heterogeneously functionalized glycodendrimers.
Routes to heterogeneously functionalized dendrimers where the placement of end
groups is rigorously controlled (but where more synthetically intensive routes are
required) have been reported by researcher groups including those of Simanek and
Thayumanavan (Vutukuri et al. 2003; Hollink and Simanek 2006; Crampton et al.
2007). These systematic efforts will be most important for frameworks with less
flexibility (less ability to scramble carefully placed end groups) than the PAMAMs.
Ramstr¨m and Lehn (2000) used dynamic combinatorial chemistry (DCC) to form
bis-saccharides via a disulfide linkage. Products were templated in the presence of
ConA to demonstrate that DCC can be effectively used to tailor generations of syn-
thetic systems bearing multiple carbohydrates (Ramstr¨m and Lehn 2000). Although
only dimers were formed, their templated DCC could be used for larger frameworks
including dendrimers to form idealized heterosaccharide-functionalized systems.
Johansson et al. (2007) previously demonstrated combinatorial generation of glyco-
dendrimers. Although fucose was always used as the carbohydrate end group in the
current example, a large library of glycodendrimers was synthesized in which the
amino acids comprising the dendrimer branches were varied. This methodology
could be very well suited to the creation of dendrimers bearing multiple carbo-
hydrates (Johansson et al. 2007).
13.6. ELECTRON PARAMAGNETIC RESONANCE (EPR)
CHARACTERIZATION OF HETEROGENEOUSLY
FUNCTIONALIZED DENDRIMERS
In order to effectively interpret assays performed with glycodendrimers and other
ligand-bearing dendrimers with their receptors, a thorough understanding of the den-
drimer itself is required. We performed extensive studies using EPR spectroscopy
with spin-labeled dendrimers to determine the relative locations of dendrimer end
groups on heterogeneously functionalized dendrimers (Walter et al. 2005). Our
work finds its foundation in reports with spin-labeled proteins, where site-directed
spin-labeling experiments allowed for the determination of relative distances
between two spin-labeled components of proteins or peptides (Miick et al. 1992;
Hubbell et al. 1998; Berliner et al. 2001). In addition, an excellent precendent for
spin labeling of dendrimers was in place prior to our studies (Ottaviani et al. 1994;
Maliakal et al. 2003).
