Lactone-based probes and methods of use thereof
The invention provides a compound of formula I: or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , L 1 , L 2 and Y have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful for labeling penicillin-binding proteins (PBPs).
1. A compound of formula I:
or a salt thereof, wherein:
R 1 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxyl, aryl, heteroaryl, or 4-8 membered heterocycle; wherein the (C 1 -C 6 )alkyl is optionally substituted with one or more groups independently selected from halo, —OR a , —CN, —NO 2 , -oxo-, —N(R a ) 2 , —CO 2 R a , aryl, heteroaryl, or 4-8 membered heterocycle, wherein any aryl, heteroaryl, and 4-8 membered heterocycle is optionally substituted with one or more groups independently selected from halo, —OR a , —CN, —NO 2 , -oxo-, —N(R a ) 2 , or —CO 2 R a ;
R 2 is H or (C 1 -C 6 )alkyl;
R 3 is H or (C 1 -C 6 )alkyl;
R 4 is
L 1 is absent or (C 1 -C 4 )alkylene;
L 2 is absent or a linking group;
Y is (C 2 -C 6 )alkynyl, or Y comprises a core structure selected from the group consisting of rhodol, rhodamine, carboxytetramethylrhodamine, and rosamine; and
each R a is independently hydrogen or C 1-4 alkyl; or two R a groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
2. The compound or salt of claim 1 , wherein L 2 is —C(═O)NH(CH 2 ) 3 CH 2 — or —C(═O)NH(CH 2 ) 5 C(═O)NH—.
3. The compound or salt of claim 1 , wherein Y is (C 2 -C 6 )alkynyl.
4. The compound or salt of claim 1 , wherein Y comprises a core structure selected from the group consisting of rhodol, rhodamine, carboxytetramethylrhodamine, and rosamine, and an analog thereof.
5. The compound or salt of claim 1 , wherein Y is
6. A compound selected from the group consisting of:
or a salt thereof.
7. A composition comprising a compound of formula I as described in claim 1 , or a salt thereof, and an excipient.
8. A kit comprising:
1) a compound of formula I as described in claim 1 , or a salt thereof;
2) instructions for contacting one or more penicillin-binding protein (PBPs) with the compound to provide one or more labeled PBPs; and
3) instructions for detecting the labeled PBPs.
9. The compound of claim 1 , wherein the group
is selected from the group consisting of:
10. The compound of claim 1 , wherein the group
is selected from the group consisting of: