title: Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS.
abstract: Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery, leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.
authors.affiliation: Chemistry, University of Southampton, Southampton, SO17 1BJ, UK. dch2@soton.ac.uk ali1@soton.ac.uk.
authors.forename: D J
authors.initials: DJ
authors.lastname: Asby
authors.affiliation: Chemistry, University of Southampton, Southampton, SO17 1BJ, UK. dch2@soton.ac.uk ali1@soton.ac.uk and Institute of Chemical and Engineering Sciences, A*Star, 138665, Singapore.
authors.forename: M G
authors.initials: MG
authors.lastname: Radigois
authors.affiliation: Chemistry, University of Southampton, Southampton, SO17 1BJ, UK. dch2@soton.ac.uk ali1@soton.ac.uk.
authors.forename: D C
authors.initials: DC
authors.lastname: Wilson
authors.affiliation: Chemistry, University of Southampton, Southampton, SO17 1BJ, UK. dch2@soton.ac.uk ali1@soton.ac.uk.
authors.forename: F
authors.initials: F
authors.lastname: Cuda
authors.affiliation: Institute of Chemical and Engineering Sciences, A*Star, 138665, Singapore and Department of Pharmacy, National University of Singapore, 117543, Singapore.
authors.forename: C L L
authors.initials: CL
authors.lastname: Chai
authors.affiliation: Institute of Chemical and Engineering Sciences, A*Star, 138665, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Chen
authors.affiliation: School of Clinical Sciences, University of Bristol, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Bienemann
authors.affiliation: Chemistry, University of Southampton, Southampton, SO17 1BJ, UK. dch2@soton.ac.uk ali1@soton.ac.uk.
authors.forename: M E
authors.initials: ME
authors.lastname: Light
authors.affiliation: Chemistry, University of Southampton, Southampton, SO17 1BJ, UK. dch2@soton.ac.uk ali1@soton.ac.uk.
authors.forename: D C
authors.initials: DC
authors.lastname: Harrowven
authors.affiliation: Chemistry, University of Southampton, Southampton, SO17 1BJ, UK. dch2@soton.ac.uk ali1@soton.ac.uk and The Institute for Life Sciences, University of Southampton, Southampton, UK.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-7420-5063
authors.initials: A
authors.lastname: Tavassoli
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D061986:MCF-7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; D017382:Reactive Oxygen Species; C477578:cribrostatin 6