Compounds and methods for scavenging dicarbonyl electrophiles
Inventors
Wilson, Keith T. • Oates, John A. • Boutaud, Olivier • Amarnath, Venkataraman • Carrier, Erica J. • Gobert, Alain P.
Assignees
US Department of Veterans Affairs • Vanderbilt University
Publication Number
US-11696903-B2
Publication Date
2023-07-11
Expiration Date
2040-06-04
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Abstract
Compounds and methods of scavenging bifunctional electrophiles and reducing the occurrence of lysyl-levuglandin adducts in a subject in need thereof by administering a levuglandin adduct formation inhibiting amount of a compound of the following formula: wherein the variables are defined herein.
Core Innovation
The invention relates to compounds and methods for scavenging bifunctional electrophiles, specifically dicarbonyl electrophiles such as levuglandins that are generated in vivo during carcinogenesis. The compounds inhibit the formation of levuglandin adducts on lysine residues of proteins and DNA in a subject, thereby reducing mutagenesis and somatic genomic abnormalities associated with these adducts.
The problem addressed is the unclear molecular process by which healthy colonic epithelial cells transform into cancer cells, despite known roles of inflammation, COX-2 activity, and reactive electrophiles. Particularly, the formation of levuglandin adducts on histones and DNA contributes to genomic instability, epigenetic dysregulation, and suppression of antitumoral immunity, but prior to this invention, effective methods to inhibit these pathological modifications were not established.
The invention provides potent scavengers, including compounds such as 2-hydroxybenzylamine (2-HOBA) and 5-ethyl-2-hydroxybenzylamine (EtHOBA), which react rapidly with dicarbonyl electrophiles to prevent adduct formation. These compounds have demonstrated efficacy in models of colorectal cancer and Helicobacter pylori-induced gastric cancer by reducing electrophile adducts, tumor development, dysplasia, and enhancing the antitumoral immune response without inhibiting COX-2 activity itself.
Claims Coverage
The patent includes two independent claims covering methods of inhibiting gastrointestinal cancer progression and mitigating pre-malignant lesions by administering specific compounds that inhibit levuglandin adduct formation.
Method of inhibiting gastrointestinal cancer progression induced by Helicobacter pylori immune response
Administering to a subject a levuglandin adduct formation inhibiting amount of a compound of a specified formula that includes substitutions at positions R1, R2, R3, R4, and R5 as defined in the patent to inhibit progression of gastrointestinal cancer induced by Helicobacter pylori infection immune response.
Method of mitigating progression of pre-malignant lesions induced by Helicobacter pylori immune response
Administering an effective amount of a compound of a specified formula with defined substituents to a subject in need thereof to mitigate progression of pre-malignant lesions in the gastrointestinal tract.
Method of treating or inhibiting progression of gastrointestinal carcinoma
Administering an effective Helicobacter pylori infection reducing amount of a compound of a defined formula to a subject in need thereof for treatment or inhibition of gastrointestinal carcinoma.
The independent claims collectively cover methods of using specified levuglandin scavenging compounds to inhibit the progression of gastrointestinal cancers and pre-malignant conditions induced by Helicobacter pylori infection by lowering levuglandin adduct formation, with particular mention of colorectal cancer and specified chemical structures including 2-hydroxybenzylamine and its analogs.
Stated Advantages
The compounds effectively scavenge bifunctional electrophiles, preventing formation of protein and DNA adducts that contribute to carcinogenesis.
They reduce tumor development and dysplasia in animal models, including colorectal and gastric cancer models.
The compounds enhance antitumoral immune responses, restoring immune cell infiltration and increasing expression of immune mediators in tumor tissues.
They prevent histone modification by levuglandins without inhibiting COX-2 enzymatic activity, avoiding side effects related to COX-2 inhibition.
Documented Applications
Treatment and prevention of colorectal cancer, including colitis-associated carcinoma.
Mitigating progression of pre-malignant lesions in the gastrointestinal tract, including the colon and esophagus.
Inhibition of Helicobacter pylori-induced gastric carcinogenesis and associated intramucosal carcinoma.
Prevention of further mutations and cellular transformation to malignancy in colon, esophagus, breast, lung, pancreas, gastrointestinal tract, and prostate cancers.
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