Bis-sulfhydryl macrocyclization systems

摘要

Peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production are described.

主权项

1. A peptidomimetic macrocycle of Formula (I):wherein:
each A, C, D, and E is independently a natural or non-natural amino acid; each B is independently a natural or non-natural amino acid,  [—NH-L4-CO—], [—NH-L4-SO2—], or [—NH-L4-]; R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, unsubstituted or substituted with R5; L1, L3 and L4 are independently alkylene, alkenylene, alkynylene, heteroalkylene, heterocycloalkylene, or [—R4—K—R4—]n, each being unsubstituted or substituted with R5; L2 is a linker moiety unsubstituted or substituted with R5; each K is independently O, S, SO, SO2, CO, CO2, or CONR3; each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each R5 is independently halogen, alkyl unsubstituted or substituted with halogen, —OR6, —N(R6)2, —SR6, —SORE, —SO2R6, —CO2R6, a fluorescent label, a radioisotope or a therapeutic agent; each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent label, a radioisotope or a therapeutic agent; R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, unsubstituted or substituted with R5, or part of a cyclic structure with a D residue; R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, unsubstituted or substituted with R5, or part of a cyclic structure with an E residue; v is an integer from 1-1000; w is an integer from 1-1000; x is an integer from 0-10; y is an integer from 0-10; z is an integer from 0-10; each n is independently an integer from 1-5; and x+y+z is at least 3,wherein at least one of A, B, C, D, or E, is an amino acid with a side chain thiol moiety.