Modular synthesis of nimbolide and its analogues as PARP1 trapping inducers

PARP1 inhibitors (PARPi) has reshaped the clinical treatment of cancer patients with germline BRCA1/2 mutations presumably due to their ability to induce PARP1 trapping. Since PARPi resistance is frequently observed, there is still an unmet need to develop next generation PARP1-targeting agents for a more complete and sustained therapeutic effect. Historically, natural products have played pivotal roles in anticancer drug development by providing novel targets and mechanism of actions. In our recent discovery20, a ring seco-C limonoid natural product, nimbolide, was found to inhibit a Poly-ADPRibosylation (PARylation)-dependent ubiquitin E3 ligase RNF114, and in doing so, induce the “super trapping” of both PARylated PARP1 and PAR-dependent DNA repair factors. Modular access to nimbolide and its analogues represents an opportunity to develop novel agents as the second generation PARP1-targeting agents for the treatment of BRCA-deficient cancers. Here, we report a convergent synthesis of nimbolide through a pharmacophore-directed, late-stage coupling strategy. The broad generality of this route is demonstrated through the synthesis of a variety of analogues with their preliminary cellular cytotoxicity and PARP1 trapping activity reported.