Synthesis of nimbolide and its analogues and their application as poly(ADP-ribose) polymerase-1 trapping inducers

Nimbolide, a ring seco-C limonoid natural product, was recently found to inhibit the poly(ADP)-ribosylation (PARylation)-dependent ubiquitin E3 ligase RNF114. In doing so, it induces the ‘supertrapping’ of both PARylated PARP1 and PAR-dependent DNA-repair factors. PARP1 inhibitors have reshaped the treatment of cancer patients with germline BRCA1/2 mutations partly through the PARP1 trapping mechanism. To this end, modular access to nimbolide analogues represents an opportunity to develop cancer therapeutics with enhanced PARP1 trapping capability. Here we report a convergent synthesis of nimbolide through a late-stage coupling strategy. Through a sulfonyl hydrazone-mediated etherification and a radical cyclization, this strategy uses a pharmacophore-containing building block and diversifiable hydrazone units to enable the modular synthesis of nimbolide and its analogues. The broad generality of our synthetic strategy allowed access to a variety of analogues with their preliminary cellular cytotoxicity and PARP1 trapping activity reported. Nimbolide is an inhibitor of poly(ADP)-ribosylation-dependent ubiquitin E3 ligase RNF114. A modular synthesis of nimbolide and its analogues is now reported, using a sulfonyl hydrazone-mediated etherification and a radical cyclization strategy. These analogues give insight into structure–activity relationships and some have superior poly(ADP-ribose) polymerase-1 trapping activity relative to nimbolide.