US 2021/0275560 A1 · AZITHROMYCIN AND ROXITHROMYCIN DERIVTIVES AS SENOLYTIC DRUGS

Abstract

This disclosure describes the use of azithromycin, roxithromycin, and telithromycin, including derivatives thereof, as senolytic drugs. BrdU was used to induce senescence in model human fibroblast cell lines. Also disclosed are methods for screening compounds for senolytic activity. The SRB assay was used to measure cell viability through protein content. Azithromycin roxithromycin, and telithromycin, clinically-approved pharmaceuticals, were found to be senolytic drugs. However, the closely-related parent compound, erythromycin, showed no senolytic activity. Azithromycin strongly induced both aerobic glycolysis and autophagy in human fibroblasts, but showed bi-phasic effects including on mitochondrial oxygen consumption rates with inhibitory activity at 50 μM and stimulatory activity at 100 μM. The xCELLigence real-time assay system showed that azithromycin preferentially targets senescent cells, removing approximately 97% (nearly a 25-fold reduction in senescent cells).

Claims50

Dependent claims

A senolytic composition comprising a pharmaceutically effective amount of a compound having a formula selected from

wherein R1 and R2 may be the same or different, and are selected from a membrane-targeting signal, a mitochondria-targeting signal, hydrogen, carboxyl, an alkane, a cyclic alkane, an alkane-based derivative, an alkene, a cyclic alkene, an alkene-based derivative, an alkyne, an alkyne-based derivative, a ketone, a ketone-based derivative, an aldehyde, an aldehyde-based derivative, a carboxylic acid, a carboxylic acid-based derivative, an ether, an ether-based derivative, an ester, an ester-based derivative, an amine, an amino-based derivative, an amide, an amide-based derivative, a monocyclic arene, a polycyclic arene, a heteroarene, an arene-based derivative, a heteroarene-based derivative, a phenol, a phenol-based derivative, a benzoic acid, and a benzoic acid-based derivative;
and
at least one of R1 and R2 is one of a membrane-targeting signal selected from palmitic acid, stearic acid, myristic acid, and oleic acid, a short-chain fatty acid, and a medium-chain fatty acid and a TPP-derivative.

Dependencies are inferred from the claim text.

Azithromycin and roxithromycin derivtives as senolytic drugs

Life of this patent

Azithromycin and roxithromycin derivtives as senolytic drugs

Life of this patent

Abstract

Claims50