Fluorogenic amino acids
AssigneePresident and Fellows of Harvard College
InventorsErkin Kuru, Jonathan Rittichier, George M. Church
Life of this patent
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Abstract
Provided herein are compounds (i.e., fluorogenic amino acids (FgAAs), e.g., compounds of Formulae (I), (II), (III), and (IV)) that can be used in fluorescent labeling of biomolecules (e.g., proteins) and/or cells. Also described herein are methods of labeling and detecting biomolecules and/or cells by incorporating the FgAA compounds described herein into the biomolecules and/or cells (e.g., by enzymatic incorporation). Also provided herein are biomolecules, cells, compositions, and kits comprising the FgAA compounds described herein.
Claims147
A compound of Formula (I):
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- ═YA is ═N+(RN1)2, ═NRN1, ═O+RO1, ═O, or ═S+RS1, or ═S;
- Ring A is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring comprising at least one double bond in conjugation with ═YA and the group:
- Ring B is optionally substituted aryl or optionally substituted heteroaryl ring;
- YB is —N(RN1)2, —ORO1, or —SRS1;
- L1 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof;
- R1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide;
- each instance of R2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide;
- or two R2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RN1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- and
- each instance of RS1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.
The compound of the preceding claim, wherein Ring A is a 6-membered optionally substituted carbocyclic or 6-membered optionally substituted heterocyclic ring.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- each of X1, X2, X3, and X4 are independently N or CR4;
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- and
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.
The compound of any one of the preceding claims, wherein X1 is CR4.
The compound of any one of the preceding claims, wherein X2 is CR4.
The compound of any one of the preceding claims, wherein X3 is CR4.
The compound of any one of the preceding claims, wherein X4 is CR4.
The compound of any one of the preceding claims, wherein Ring A is an optionally substituted C6 carbocyclic ring.
The compound of any one of the preceding claims, wherein Ring A is an optionally substituted cyclohexadienyl ring.
The compound of any one of the preceding claims, wherein Ring A is of the formula:
- wherein:
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and
- m is 0, 1, 2, 3, or 4.
The compound of any one of the preceding claims, wherein Ring B is optionally substituted aryl.
The compound of any one of the preceding claims, wherein Ring B is optionally substituted phenyl.
The compound of any one of the preceding claims, wherein Ring B is of the formula:
- wherein:
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and
- m is 0, 1, 2, 3, or 4.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein ═YA is ═N+(RN1)2.
The compound of any one of the preceding claims, wherein ═YA is ═O.
The compound of any one of the preceding claims, wherein YB is —N(RN1)2.
The compound of any one of the preceding claims, wherein YB is —ORO1.
The compound of any one of the preceding claims, wherein the compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein L1 is optionally substituted alkylene.
The compound of any one of the preceding claims, wherein L1 is optionally substituted C1-6 alkylene.
The compound of any one of the preceding claims, wherein L1 is unsubstituted C1-6 alkylene.
The compound of any one of the preceding claims, wherein L1 is of the formula:
The compound of any one of the preceding claims, wherein L1 is of the formula:
The compound of any one of the preceding claims, wherein L1 is of the formula:
The compound of any one of the preceding claims, wherein L1 is of the formula:
The compound of any one of the preceding claims, wherein the compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- n is an integer from 1-6, inclusive.
The compound of any one of the preceding claims, wherein the compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- n is an integer from 1-6, inclusive.
The compound of any one of the preceding claims, wherein the compound is of the following formula:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- n is an integer from 1-6, inclusive.
The compound of any one of the preceding claims, wherein each instance of m is 0.
The compound of any one of the preceding claims, wherein at least one instance of RN1 is optionally substituted alkyl.
The compound of any one of the preceding claims, wherein at least one instance of RN1 is optionally substituted C1-6 alkyl.
The compound of any one of the preceding claims, wherein at least one instance of RN1 is unsubstituted C1-6 alkyl.
The compound of any one of the preceding claims, wherein at least one instance of RN1 is methyl.
The compound of any one of the preceding claims, wherein each instance of RN1 is methyl.
The compound of any one of the preceding claims, wherein at least one instance of RO1 is hydrogen.
The compound of any one of the preceding claims, wherein the compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- n is an integer from 1-6, inclusive.
The compound of any one of the preceding claims, wherein the compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- n is an integer from 1-6, inclusive.
The compound of any one of the preceding claims, wherein the compound is of the following formula:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
The compound of any one of the preceding claims, wherein n is 1, 2, or 3.
The compound of any one of the preceding claims, wherein the compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein the compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein R1 is hydrogen.
The compound of any one of the preceding claims, wherein at least one instance of R2 is hydrogen.
The compound of any one of the preceding claims, wherein each instance of R2 is hydrogen.
A compound of Formula (II):
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- Ring D is optionally substituted aryl or optionally substituted heteroaryl;
- R3 is hydrogen, ═NRNX, —N—RNX, ═S, —S−, ═O, —O−, ═C(RC)2, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl;
- is a single or double bond, provided that when is a single bond, R3 is ═NRNX ═S, ═O or ═C(RC)2, and provided that when is a double bond, R3 is not ═NRNX, ═S, ═O or ═C(RC)2;
- Ring C is an optionally substituted heterocyclic or heteroaryl ring comprising at least one N, S, or O atom;
- wherein the heterocyclic or heteroaryl ring is in conjugation with the group:
- Ring C is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring substituted with YC and comprising at least one double bond in conjugation with YC and the group:
- YC is —N(RN1)2, ═N+(RN1)2, ═NRN12—ORO1, ═O+RO1, ═O, —SRS1, ═S+RS1, or ═S;
- Y is a bond, —O—, —NRN2—, or —S—;
- L2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof;
- R1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide;
- each instance of R2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide;
- or two R2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RN1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- RN2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- RNX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- each instance of RO1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and
- each instance of RC is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl;
- optionally wherein two RC on the same carbon atom are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.
The compound of any one of the preceding claims, wherein Ring C is a 6-membered optionally substituted carbocyclic or 6-membered optionally substituted heterocyclic ring substituted with YC.
The compound of any one of the preceding claims, wherein the compound is of one of the following formula:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- each of X1, X2, X3, and X4 are independently N or CR4;
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- and
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and
- m is 0, 1, 2, 3, or 4.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein X1 is CR4.
The compound of any one of the preceding claims, wherein X2 is CR4.
The compound of any one of the preceding claims, wherein X3 is CR4.
The compound of any one of the preceding claims, wherein X4 is CR4.
The compound of any one of the preceding claims, wherein Ring C is an optionally C6 carbocyclic ring.
The compound of any one of the preceding claims, wherein Ring C is an optionally substituted cyclohexadienyl ring.
The compound of any one of the preceding claims, wherein Ring C is of the formula:
- wherein:
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and
- m is 0, 1, 2, 3, or 4.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein ═YC is ═N+(RN1)2.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof,
- wherein n is an integer from 1-6, inclusive.
The compound of any one of the preceding claims, wherein the compound is of the following formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6.
The compound of any one of the preceding claims, wherein at least one instance of RN1 is hydrogen.
The compound of any one of the preceding claims, wherein each instance of RN1 is hydrogen.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein Ring C is an optionally substituted heterocyclic ring.
The compound of any one of the preceding claims, wherein Ring C is an optionally substituted 5-membered heterocyclic ring.
The compound of any one of the preceding claims, wherein Ring C is of the formula:
- wherein each of G1, G2, G3, and G4 is independently selected from the group consisting of O, S, and NRN3;
- and
- each instance of RN3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein Ring D is optionally substituted aryl.
The compound of any one of the preceding claims, wherein Ring D is optionally substituted phenyl.
The compound of any one of the preceding claims, wherein Ring D is of the formula:
- wherein:
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and m is 0, 1, 2, 3, or 4.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein G1 is S.
The compound of any one of the preceding claims, wherein G2 is NRN3.
The compound of any one of the preceding claims, wherein G3 is S.
The compound of any one of the preceding claims, wherein G4 is O.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein Y is —NRN2—.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein L2 is optionally substituted alkylene.
The compound of any one of the preceding claims, wherein L2 is optionally substituted C1-6 alkylene.
The compound of any one of the preceding claims, wherein L2 is unsubstituted C1-6 alkylene.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof,
- wherein n is an integer from 1-6, inclusive.
The compound of any one of the preceding claims, wherein each instance of m is 0.
The compound of any one of the preceding claims, wherein each instance of R4 is hydrogen.
The compound of any one of the preceding claims, wherein RN2 is hydrogen.
The compound of any one of the preceding claims, wherein each instance of RN3 is hydrogen.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein n is 1, 2, or 3.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically labeled derivative thereof.
The compound of any one of the preceding claims, wherein R1 is hydrogen.
The compound of any one of the preceding claims, wherein at least one instance of R2 is hydrogen.
The compound of any one of the preceding claims, wherein each instance of R2 is hydrogen.
The compound of any one of the preceding claims, wherein is a single bond;
- and
- R3 is ═O.
The compound of any one of the preceding claims, wherein a double bond.
The compound of any one of the preceding claims, wherein is a double bond;
- and
- R3 is hydrogen.
The compound of any one of the preceding claims, wherein the compound is selected from the group consisting of:
- and salts, tautomers, and isotopically labeled derivatives thereof.
A compound of Formula (III):
- and salts, tautomers, and isotopically labeled derivatives thereof, wherein:
- R3 is ═NRNX, ═S, ═O, or ═C(RC)2;
- —YC is —N(RN1)2, —ORO1, or —SRS1;
- L2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof;
- R1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide;
- each instance of R2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide;
- or two R2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RN1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- RN2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- RNX is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- each instance of RO1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- each instance of RC is independently hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl, optionally wherein two RC on the same carbon atom are joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl;
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and
- m is 0, 1, 2, 3, or 4.
The compound of any one of the preceding claims, wherein compound is of one of the following formulae:
- or a salt, tautomer, or isotopically labeled derivative thereof.
A compound of Formula (IV):
- or a salt, tautomer, or isotopically labeled derivative thereof, wherein:
- Ring C is an optionally substituted aryl ring, or optionally substituted heteroaryl ring comprising at least one N, S, or O atom;
- wherein Ring C is substituted with —YC;
- YC is —N(RN1)2, —ORO1, —SRS1,
- each of G1, G3, and G4 is independently selected from the group consisting of O, S, and NRN3;
- G2 is N;
- R3 is hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted acyl;
- L2 is a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted arylene, optionally substituted heterocyclylene, optionally substituted heteroarylene, optionally substituted acylene, or a combination thereof;
- R1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, an oxygen protecting group, an amino acid, or a polypeptide;
- each instance of R2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, a nitrogen protecting group, an amino acid, or a polypeptide;
- or two R2 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RN1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN1 bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- each instance of RN3 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group.
The compound of any one of the preceding claims, wherein the compound is of the formula:
- or a salt, tautomer, or isotopically derivative thereof, wherein:
- each instance of R4 is independently hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl optionally substituted sulfonyl, optionally substituted sulfinyl, sulfate, sulfonate, —N(RN)2, —ORO, or —SRS;
- each instance of RN is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group;
- or two RN bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl;
- each instance of RO is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group;
- each instance of RS is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group;
- and
- m is 0, 1, 2, 3, or 4.
The compound of any one of the preceding claims, wherein the compound is one of the following formulae:
- or a salt, tautomer, or isotopically derivative thereof.
The compound of any one of the preceding claims, wherein the compound is a D-amino acid.
The compound of any one of the preceding claims, wherein the compound is an L-amino acid.
A composition comprising a compound of any one of the preceding claims;
- and a solvent or excipient.
A biomolecule comprising a compound of any one of the preceding claims, or a salt or a tautomer thereof, wherein the compound is covalently attached to to the biomolecule.
The biomolecule of any one of the preceding claims, wherein the biomolecule is a protein, polypeptide, glycan, peptidoglycan, antibody, or nucleic acid.
The biomolecule of any one of the preceding claims, wherein the biomolecule is a protein.
The biomolecule of any one of the preceding claims, wherein the biomolecule is peptidoglycan.
A cell comprising a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof.
The cell of any one of the preceding claims, wherein the cell is a mammalian cell.
The cell of any one of the preceding claims, wherein the cell is a bacterial cell.
A method of labeling a biomolecule, the method comprising exposing the biomolecule and/or cell to a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof.
The method of any one of the preceding claims, wherein the compound is covalently incorporated into the biomolecule.
The method of any one of the preceding claims, wherein the compound is incorporated into biomolecule via enzymatic incorporation.
The method of any one of the preceding claims, where the compound is incorporated into the biomolecule through transpeptidation.
The method of any one of the preceding claims, wherein the compound is incorporated into a protein, polypeptide, or peptidoglycan via transpeptidation.
The method of any one of the preceding claims, wherein the compound is incorporated into peptidoglycan.
The method of any one of the preceding claims, where the compound is incorporated into the biomolecule and/or cell through D,D-transpeptidation or L,D-transpeptidation.
A method of labeling a cell, the method comprising exposing the cell to a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof.
The method of any one of the preceding claims, wherein the compound is covalently incorporated into the cell.
The method of any one of the preceding claims, wherein the compound is incorporated into the cell via enzymatic incorporation.
The method of any one of the preceding claims, where the compound is incorporated into the cell through transpeptidation.
The method of any one of the preceding claims, wherein the compound is incorporated into a protein, polypeptide, or peptidoglycan via transpeptidation.
The method of any one of the preceding claims, wherein the compound is incorporated into peptidoglycan.
The method of any one of the preceding claims, where the compound is incorporated into the biomolecule and/or cell through D,D-transpeptidation or L,D-transpeptidation.
A method of detecting a biomolecule and/or cell comprising:
- (a) labeling the biomolecule or cell according to a method of any one of the preceding claims;
- and
- (b) measuring the fluorescence of the biomolecule and/or cell.
The method of any one of the preceding claims, wherein the biomolecule is a protein, polypeptide, or peptidoglycan
A method of detecting a labeled biomolecule or cell of any one of the preceding claims, the method comprising measuring or observing the fluorescence of the biomolecule or cell.
The method of any one of the preceding claims, wherein the biomolecule is a protein.
The method of any one of the preceding claims, wherein the biomolecule is peptidoglycan.
The method of any one of the preceding claims, wherein the cell is mammalian cell.
The method of any one of the preceding claims, wherein the cell is a bacterial cell.
A kit comprising a compound of any one of the preceding claims, or a salt, tautomer, or isotopically labeled derivative thereof, or a composition thereof;
- and one or more chemical reagents or enzymes.
Dependencies are inferred from the claim text.