Abstract
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. (Figure presented.)
Original language | English (US) |
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Pages (from-to) | 378-385 |
Number of pages | 8 |
Journal | Nature Synthesis |
Volume | 3 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2024 |
ASJC Scopus subject areas
- Chemistry (miscellaneous)
- Inorganic Chemistry
- Organic Chemistry
- Materials Chemistry