Enantiopure hydroxymethylated cycloalkenols as privileged small molecular multifunctional scaffolds for the asymmetric synthesis of carbocycles

Kumar, Rajan; Rej, Rohan Kalyan; Halder, Joydev; Mandal, Haridas; Nanda, Samik

doi:10.1016/j.tetasy.2016.05.003

Cited by 3 publications

(1 citation statement)

References 34 publications

(66 reference statements)

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“…The crude mixture was SiO 2 purified with EtOAc (30–100%) in hexanes to afford a clear oil (0.46 g, 80% yield). 1 H NMR analysis was consistent with that reported previously. − …”

Section: Methodssupporting

confidence: 90%

Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile

et al. 2016

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The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant towards small molecule inhibition despite the substantial number of compounds known to inhibit upstream proteins in the activation pathway. Given the roles of many of these upstream proteins in multiple biochemical pathways, targeting the p50/p65 heterodimer offers an opportunity for enhanced on-target specificity. Towards this end, the p65 protein presents two non-disulfide cysteines, Cys38 and Cys120, at its DNA-binding interface that are amenable to targeting by covalent molecules. The natural product helenalin, a sesquiterpene lactone, has been previously shown to target Cys38 on p65 and ablate its DNA-binding ability. Using helenalin as inspiration, simplified helenalin analogues were designed, synthesized, and shown to inhibit induced canonical NF-κB signaling in cell culture. Moreover, two simplified helenalin probes were proficient at forming covalent protein adducts, binding to Cys38 on recombinant p65, and targeting p65 in HeLa cells without engaging canonical NF-κB signaling proteins IκBα, p50, and IKKα/β. These studies further support that targeting the p65 transcription factor-DNA interface with covalent small molecule inhibitors is a viable approach towards regulating canonical NF-κB signaling.

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“…The crude mixture was SiO 2 purified with EtOAc (30–100%) in hexanes to afford a clear oil (0.46 g, 80% yield). 1 H NMR analysis was consistent with that reported previously. − …”

Section: Methodssupporting

confidence: 90%