Methods and compounds for identifying glycosyltransferase inhibitors

Patent metadata

Field	Value
Publication number	US-10106833-B2
Application number	US-201314390857-A
Country	US
Kind code	B2
Filing date	Mar 13, 2013
Priority date	Apr 6, 2012
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

The present invention provides moenomycin-based probe compounds of Formula (I) for use in screening inhibitors of bacterial glycosyltransferases. The present invention also provides bacterial glycosyltransferase screening assays using compounds of Formula (I).

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt thereof,
wherein
R 1 is -L-R P , —C(O)NH-L-R P , —CH 2 O-L-R P , or —C(O)O-L-R P ;
R 2 and R 3 are independently hydrogen, optionally substituted aliphatic, —OR 9 , —N(R 8 ) 2 , or —C(O)NHR 8 ;
R 4 is hydrogen or —WR 4a ;
W is —O— or —NH—;
R 4a is hydrogen, a hydroxyl protecting group, optionally substituted aliphatic, —C(O)R 10 , —C(O)NHR 8 , —C(═NR 8 )NHR 8 , or —C(O)OR 9 ;
R 5 is hydrogen or —NHR 8 ;
R 6 is hydrogen, —CH 3 , —CH 2 OR 9 , or —CH 2 OR CX ; wherein R CX is a carbohydrate moiety;
R 7 is hydrogen, —OR 9 , or —N(R 8 ) 2 ;
each R 8 is independently hydrogen, an amino protecting group, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R 8 groups on the same nitrogen may be taken together to form an optionally substituted heterocyclyl;
each R 9 is independently hydrogen, a hydroxyl protecting group, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;
each R 10 is independently optionally substituted aliphatic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl;
R a and R b are independently hydrogen or a hydroxyl protecting group;
G is an optionally substituted C 1-16 aliphatic group, wherein 0 to 10 methylene units are optionally replaced with —O—, —NR x —, —S—, —C(O)—, —C(═NR x ), —S(O)—, —SO 2 —, —N═N—, —C═N—, —N—O—, an optionally substituted arylene, an optionally substituted heterocyclylene, or an optionally substituted heteroarylene; wherein each instance of R x is independently hydrogen, optionally substituted aliphatic, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; or
G is a group of Formula (a), (b), or (c):

wherein a is 3, 4, or 5;

wherein
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently hydrogen or halogen;
d is an integer between 1 and 25, inclusive; and
e is an integer of between 2 and 25, inclusive;
provided the sum of d and e is greater than 16; or

wherein
Y is —O—, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;
each instance of R c is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of R d is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
R z is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR g , —SR g , —NHR g , or —N(R g ) 2 , wherein each instance of R g is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two R g groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;
each instance of n is, independently, 0, 1, 2, 3, or 4;
each instance of m is, independently, 0, 1, 2, 3, or 4; and
x is 1, 2, 3, 4, 5, or 6;
R YY is hydrogen or —OR XX ;
R XX is hydrogen, a hydroxyl protecting group, or a group of formula:

wherein
R 11 is hydrogen, optionally substituted aliphatic, —C(O)NHR 8 , —CH 2 OR 9 , or —C(O)OR 9 ;
R 12 and R 13 are independently hydrogen, optionally substituted aliphatic, —OR 9 , —N(R 8 ) 2 , or —C(O)NHR 8 ;
R 14 is hydrogen or —NHR 8 ;
R 15 is hydrogen, —C(O)NHR 8 , —CH 2 OR 9 , or —C(O)OR 9 ;
R 16 is hydrogen or —OR 9 ;
R 17 is hydrogen or —OR 9 ;
R 18 is hydrogen or —OR 9 ;
R 19a is hydrogen or —OR 9 ;
R 19b is hydrogen or —OR 9 ;

wherein a hydrogen radical on the compound of Formula (I) is replaced with -L-R P ;
L is a covalent bond, —NR y —, —N(R y )C(O)—, —N(R y )C(O)N(R y )—, —N(R y )C(S)N(R y )—, —C(O)N(R y )—, —N(R y )SO 2 —, —SO 2 N(R y )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or an optionally substituted aliphatic linker, wherein one or more methylene units of the aliphatic linker are optionally replaced by —NR y —, —N(R y )C(O)—, —N(R y )C(O)N(R y )—, —N(R y )C(S)N(R y )—, —C(O)N(R y )—, —N(R y )SO 2 —, —SO 2 N(R y )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, cycloalkylene, heterocyclylene, arylene, or heteroarylene; wherein R y is hydrogen, C 1-6 alkyl, or —C(O)C 1-6 alkyl; and
R P is selected from the group consisting of ligands, radionuclides, fluorescent dyes, chemiluminescent agents, microparticles, enzymes, calorimetric labels, magnetic labels, and haptens.

2. A compound of Formula (I):

or a salt thereof,
wherein
R 1 is hydrogen, —C(O)NHR 8 , —CH 2 OR 9 , or —C(O)OR 9 ;
R 2 and R 3 are independently hydrogen, optionally substituted aliphatic, —OR 9 , —N(R 8 ) 2 , or —C(O)NHR 8 ;
R 4 is hydrogen or —WR 4a ;
W is —O— or —NH—;
R 4a is hydrogen, a hydroxyl protecting group, optionally substituted aliphatic, —C(O)R 10 , —C(O)NHR 8 , —C(═NR 8 )NHR 8 , or —C(O)OR 9 ;
R 5 is hydrogen or —NHR 8 ;
R 6 is hydrogen, —CH 3 , —CH 2 OR 9 , or —CH 2 OR CX ; wherein R CX is a carbohydrate moiety;
R 7 is hydrogen, —OR 9 , or —N(R 8 ) 2 ;
each R 8 is independently hydrogen, an amino protecting group, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, or two R 8 groups on the same nitrogen may be taken together to form an optionally substituted heterocyclyl;
each R 9 is independently hydrogen, a

Assignees

• Harvard College

Inventors

• Kahne Daniel Evan
• Kahne Suzanne Walker
• Gampe Christian M
• Tsukamoto Hirokazu

Classifications

• C07H11/04

  Phosphates; Phosphites; Polyphosphates · CPC title

• C07H15/26

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C12Q1/48 Primary

  involving transferase · CPC title

• G01N2500/20

  cell-free systems · CPC title

• C07H13/12 Primary

  by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid · CPC title