US 2022/0089602 A1 · COMPOUNDS THAT INDUCE FERROPTIC CELL DEATH

Abstract

The diterpene natural product pleuromutilin was subjected to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

Claims20

Dependent claims

A compound of Formula I:

or a stereoisomer or salt thereof;
wherein
J is N or CH and is a single bond, or C and is a double bond;
R1 is —(C1-C6)alkyl-X, —(C2-C6)alkenyl-X, halo, OH, or heteroaryl, wherein the (C1-C6)alkyl moiety of —(C1-C6)alkyl-X is substituted optionally with halo;
X is halo, OH, or —O(C═O)CH3, or absent;
R2 and R4 are independently ORA, H, or halo, wherein RA is H, —(C1-C6)alkyl, or —(C═O)CH3;
R3 is aryl, heteroaryl, heterocycloalkyl, —(C3-C6)cycloalkyl, —(C2-C6)alkynyl, or a group comprising a fluorescent tag, wherein aryl or heteroaryl is substituted optionally with halo, OH or —(C1-C6)alkyl;
each R5 is independently CH3, —(C2-C6)alkyl or H;
W1 is O, S, or absent;
and
each W2 is independently O, S, or absent.

8 more elements

Dependencies are inferred from the claim text.

Compounds that induce ferroptic cell death

Life of this patent

Compounds that induce ferroptic cell death

Life of this patent

Abstract

Claims20