45 research outputs found
Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis
Recommended from our members
'Looking at the Others': Oscar Wilde and the Reading Gaol Archive
In looking at Wilde and the prison, scholarship has understandably focussed on the lengthy and complex De Profundis, and how the prison experience confirmed or re-shaped Wilde as a writer and thinker. Wilde himself claimed to have been saved by the ‘others’ that he encountered in prison, and these ‘others’ have received scant attention. Who were they? How does a greater knowledge of them supplement our sense of the nineteenth-century prison and of Wilde? This essay looks closely at the Reading Gaol archive, tracing out the lives of some of those with whom Wilde was incarcerated and providing analyses of the prison population in Reading while Wilde was there. Aside from yielding the only known photographs of any of the young working-class men in whom Wilde took an interest, the essay seeks to build a more nuanced reading of Wilde's experience. Above all, the aim is to open out the meanings of the Wilde myth, and, in particular, to offer a more socially inclusive version
Recommended from our members