Preparation and uses of reactive oxygen species scavenger derivatives
Compounds of Formula (I)a or (I)b: including certain quinone derivatives, and the corresponding pharmaceutical compositions, which may serve to modulate ferroptosis in a subject. Also disclosed herein are the preparations of these compounds and pharmaceutical compositions and their potential uses in the manufacture of a medicament in reducing reactive oxygen species (ROS) in a cell and for preventing, treating, ameliorating certain related disorder or a disease.
1. A compound of Formula (I)a or Formula (I)b, a pharmaceutically acceptable salts thereof, and individual enantiomers or diastereomers thereof:
wherein,
z is 0 or 1;
L is absent; or L is selected from C 1 -C 10 alkyl, C 1 -C 10 alkoxyl, C 3-7 cycloalkyl, C 1 -C 10 alkylcycloalkyl, heterocycloalkyl, C 1 -C 10 alkylheterocycloalkyl, C 5-10 aryl, C 1 -C 10 alkylaryl, C 5-10 heteroaryl, and C 1 -C 10 alkylheteroaryl;
Q is selected from:
wherein,
n is an integer selected from 0 to 10;
each of R 1 and R 2 is independently selected from hydrogen and CH 3 ;
each of R 3 and R 4 is independently selected from hydrogen and C 1 -C 5 alkyl;
each W is independently absent or is selected from O and S; and
i) when W is absent, then R 3 and R 4 , optionally, together form the following structure:
ii) when W is O, then OR 3 and OR 4 optionally, together form the following structure:
PEP is a peptidyl moiety having the following structure:
wherein,
each asterisk (*) independently denotes a chiral center in either an (S) or (R) configuration;
m is an integer selected from 0 to 10;
X 1 is selected from hydrogen, —C(═O)—OR m , —S(O)—O—R m , —S(O 2 )—O—R m , —S(O 2 )—N—(R m ) 2 and —C(═O)—N—(R m ) 2 , where R m is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkylcycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 6 alkylheterocycloalkyl, C 5 -C 10 aryl, C 1 -C 6 alkylaryl, C 5 -C 10 heteroaryl, and C 1 -C 6 alkylheteroaryl;
each of X 2 , X 3 and X 4 is independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 5 -C 6 aryl, C 1 -C 6 alkylaryl, heteroaryl, and C 1 -C 6 alkylheteroaryl;
A is absent, or A is selected from Ala, Leu, Ile, Phe, Met, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, His, Lys, Arg, Asp, Glu, and Val, each of which can be in either a D or L configuration; wherein the amino residue is either unprotected, or protected by a protecting group selected from Cbz and Fmoc; and
G is absent, or G is selected from —O—, —S—, —NH—, —NH—C(═O)—O—, —O—C(═O)—NH—, —NH—C(═O)—NH—, —NHSO 2 —, —SO—, —SO 2 —, and —NHC(═O)—.
2. The compound according to claim 1 , wherein L is C 1 -C 10 alkyl.
3. The compound according to claim 1 , wherein L is selected from C 5 -C 10 aryl and C 1 -C 10 alkylaryl.
4. The compound according to claim 1 , wherein L is selected from C 5 -C 10 heteroaryl, C 1 -C 10 alkylaryl, C 1 -C 10 alkylheteroaryl, and pyridine.
5. The compound according to claim 1 , wherein G is absent or G is selected from —NHC(═O)—, —NHC(═O)—O—, and —NHSO 2 —.
6. The compound according to claim 1 , wherein Q has the structure:
wherein,
each W is independently absent;
n is an integer from 1 to 3;
R 1 is selected from hydrogen and methyl; and
each R 3 is independently C 1-3 alkyl.
7. The compound according to claim 1 , wherein PEP has the structure:
wherein,
each asterisk (*) independently denotes a chiral center that can be either in an (S) or (R) configuration;
X 1 is selected from —C(═O)—O—R m , —S(O)—O—R m , —S(O 2 )—O—R m , —S(O 2 )—N—(R m ) 2 , and —C(═O)—N—(R m ) 2 , where R m is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkylcycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 6 alkylheterocycloalkyl, C 5 -C 10 aryl, C 1 -C 6 alkylaryl, C 5 -C 10 heteroaryl, and C 1 -C 6 alkylheteroaryl;
each of X 2 , X 3 and X 4 is independently selected from C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 5 -C 6 aryl, C 1 -C 6 alkylaryl, C 5 -C 6 heteroaryl, and C 1 -C 6 alkylheteroaryl; and
A is absent or A is selected from Ala, Leu, Ile, Phe, Met, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, His, Lys, Arg, Asp, Glu, and Val, each of which can be in either a D or L configuration; wherein the amino residue is either unprotected, or protected by a protecting group selected from Cbz and Fmoc.
8. The compound according to claim 7 , wherein A is absent or A is valine.
9. The compound according to claim 7 , wherein,
X 1 is absent, or X 1 is selected from Et-O—C(═O)—, i-Pr-O—C(═O)—, t-Bu-O—C(═O)—, and cyclopropyl-CH 2 —O—C(═O)—;
X 2 is selected from i-propyl-CH 2 —, cyclopropyl-CH 2 —, cyclopentyl-CH 2 —, and adamantyl-CH 2 —;
X 3 is selected from Ph-CH 2 — and Pyr-CH 2 —; and
X 4 is selected from i-propyl-CH 2 —, cyclopropyl-CH 2 —, and cyclopentyl-CH 2 —.
10. The compound according to claim 7 , wherein,
A is absent;
X 1 is selected from t-Bu-O—C(═O)—, cyclopropyl-CH 2 —O—C(═O)—, and ethyl-CH 2 —O—C(═O)—;
X 2 is i-propyl-CH 2 —;
X 3 is Ph-CH 2 —; and
X 4 is i-propyl-CH 2 —.
11. The compound according to claim 7 , wherein,
A is absent;
X 1 is t-Bu-O—C(═O)—;
X 2 is selected from i-propyl-CH 2 —, and adamantyl-CH 2 —;
X 3 is Ph-CH 2 —; and
X 4 is selected from cyclopropyl-CH 2 —, cyclopentyl-CH 2 —, and i-propyl-CH 2 —.
12. The compound according to claim 7 , wherein,
A is valine;
X 1 is selected from t-Bu-O—C(═O)— and cyclopropyl-CH 2 —O—C(═O)—;
X 2 is selected from i-propyl-CH 2 — and adamantly-CH 2 —;
X 3 is Ph-CH 2 —; and
X 4 is selected from i-propyl-CH 2 —, cyclopropyl-CH 2 —, and cyclopentyl-CH 2 —.
13. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable of any of the foregoing.
14. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.