Cyanopyridylalanines are non-canonical amino acids that react with aminothiol compounds under physiological conditions in a biocompatible manner without requiring added catalyst. Here we present newly developed aminoacyl-tRNA synthetases for genetic encoding of meta-and para-cyanopyridylalanine to enable the site-specific attachment of a wide range of different functionalities. The outstanding utility of the cyanopyridine moiety is demonstrated by examples of i) post-translational functionalization of proteins, ii) in-cell macrocyclization of peptides and proteins, and iii) prootein stapling. The biocompatible nature of the protein ligation chemistry enabled by the cyanopyridylalanine amino acid opens a new path to specific in vivo protein modifications in complex biological environments.
Bicyclic peptides possess superior properties for drug discovery; however, their chemical synthesis is not straightforward and often neither biocompatible nor fully orthogonal to all canonical amino acids. The selective reaction between 1,2-aminothiols and 2,6dicyanopyridine allows direct access to complex bicyclic peptides in high yield. The process can be fully automated using standard solid-phase peptide synthesis. Bicyclization occurs in water at physiological pH within minutes and without the need for a catalyst. The use of various linkers allows tailored bicyclic peptides with qualities such as plasma stability, conformational preorganization, and high target affinity. We demonstrate this for a bicyclic inhibitor of the Zika virus protease NS2B-NS3 as well as for bicyclic versions of the α-helical antimicrobial peptide aurein 1.2.
The first broad spectrum dendralene synthesis permits the widest structural and substituent variation and promotes applications in step economic synthesis.
Diene-transmissive Diels–Alder
(DTDA) sequences are extraordinarily
powerful processes for the generation of fused bicyclic systems. Nonetheless,
only stable dienophiles have previously been deployed. Herein we report
DTDA sequences with a variety of substituted [3]dendralenes in the
first study to deploy arynes as dienophiles. We demonstrate the one-flask
generation of complex, aromatic-ring-containing, multicyclic systems
of relevance to medicinal chemistry. These synthetic operations provide
numerous successful examples of the otherwise challenging and rarely
reported intermolecular Diels–Alder reaction of acyclic 1,3-butadienes
with arynes, which is made possible due to the exalted reactivity
of dendralenic dienes.
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