title: Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs.
abstract: Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells over nontransformed cell types. Structure/activity relationships suggest that the electrophilicity of the C2-C3 olefin is critical for the observed effects on cells. Furthermore, we show that analogs lacking a reactive C7-C8 olefin can elevate ROS to levels observed with piperlongumine but show markedly reduced cell death, suggesting that ROS-independent mechanisms, including cellular cross-linking events, may also contribute to piperlongumine's induction of apoptosis. In particular, we have identified irreversible protein glutathionylation as a process associated with cellular toxicity. We propose a mechanism of action for piperlongumine that may be relevant to other small molecules having two sites of reactivity, one with greater and the other with lesser electrophilicity.
authors.affiliation: Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. dadams@broadinstitute.org
authors.forename: Drew J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Mingji
authors.initials: M
authors.lastname: Dai
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pellegrino
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Stern
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000475:Alkenes / Q000737:chemistry; D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008956:Models, Chemical; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds / Q000737:chemistry; D010881:Piperidones
chemical_list: D000255:Adenosine Triphosphate; D000475:Alkenes; D000970:Antineoplastic Agents; D004148:Dioxolanes; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C498077:piperlongumine; D010881:Piperidones