Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs - Designing Receptors for the Next Generation of Biosensors - page 41

Fig. 10 Tripodal anion receptors with association constants measured in acetonitrile
Fig. 11 Previously studied amidopyrroles and new tetrazole containing anion binders
the binding of the guest is dramatic. Comparison with other recognition elements
appended to the same scaffold reveals that this host is among the strongest neutral
binders of anions ever reported—even comparable to triply cationic hosts such as
16 [ 53 ] (Fig. 10 ).
Further inspiration from medicinal chemistry was found in the natural product
prodigiosin and its synthetic analogs (prodigiosenes), which are being heavily
investigated as novel therapeutics in a variety of contexts and whose highly potent
binding of anions are linked to their biological activities [ 54 ] . The core anion-
binding motif of prodigiosenes is a 2,2 0 -bipyrrole; prior lessons, the shape-
preferences, and anion-binding potencies of tetrazoles suggested the utility of a
scaffold in which tetrazoles are installed next to a neighboring, conjugated pyrrole.
5-(Pyrrolyl)-tetrazole (17) is a small fragment that satisfies these design criteria
(Fig. 11 )[ 55 ]. The recognition properties of the tetrazole are revealed by
comparisons to two key relatives, 2,2 0 -bipyrrole (18), which reproduces the geom-
etry of 17 with a nearly isosteric tetrazole-for-pyrrole swap and a simple
amidopyrrole (19), which is a representative member of a larger family of
amidopyrroles that have been shown to bind and transport anions. Compound 16
binds almost any anion with tenfold greater affinity than the structurally related
bipyrrole (18) (Table 2 ). The similar selectivity trends observed for 17 and 18
suggest that their structures and directional hydrogen bonding are similar and that
the acidity of the tetrazole is the key to higher affinities. Compound 17 also binds
anions at least 47-fold stronger than amidopyrroles. The tridentate 2,5-(bis-
tetrazolyl)-pyrrole (20) was also produced and compared to a forerunner that used
bis(amido)pyrroles for anion binding (21) [ 56 ]. Affinities improved again—this
time by two orders of magnitude. These amide-to-tetrazole comparisons revealed