A 1,4-linked triazole/amide based peptidomimetic macrocycle, synthesized from a triazole amide oligomer of cis-furanoid sugar triazole amino acids, possesses a conformation resembling the D-,L-α-amino acid based cyclic peptides despite having uniform backbone chirality. It undergoes a unique mode of self-assembly through an antiparallel backbone to backbone intermolecular H-bonding involving amide NH and triazole N2/N3 as well as parallel stacking via amide NH and carbonyl oxygen H-bonding, leading to the formation of a tubular nanostructure.
We report here the
preparation of an aminoxy amide-based pseudopeptide-derived
building block using furanoid sugar molecules. Through the cyclo-oligomerization
reaction, we generate a hybrid triazole/aminoxy amide macrocycle using
the as-prepared building block. The novel conformation of the macrocycle
has been characterized using NMR and molecular modeling studies, which
show a strong resemblance of our synthesized compound to
d
-,
l
-α-aminoxy acid-based cyclic peptides that contain
uniform backbone chirality. We observe that the macrocycle can efficiently
and selectively bind Cl
–
ion and transport Cl
–
ion across a lipid bilayer.
1
H NMR anion
binding studies suggest a coherent relationship between the acidity
of aminoxy amide N–H and triazole C–H proton binding
strength. Using time-based fluorescence assay, we show that the macrocycle
acts as a mobile transporter and follows an antiport mechanism. Our
synthesized macrocycle imposes cancer cell death by disrupting ionic
homeostasis through Cl
–
ion transport. The macrocycle
induced cytochrome c leakage and changes in mitochondrial membrane
potential along with activation of family of caspases, suggesting
that the cellular apoptosis occurs through a caspase-dependent intrinsic
pathway. The present results suggest the possibility of using the
macrocycle as a biological tool of high therapeutic value.
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