Synthesis and discovery of simplified pleurotin analogs bearing tricyclic core as novel thioredoxin reductase inhibitors

Abstract

Pleurotin (1) is a benzoquinone meroterpenoid known for its wide-spectrum antitumor and antibiotic activities, notably acting as natural inhibitors of the thioredoxin reductase (TrxR). Pleurotin (1) has been chemically synthesized, but only in milligram quantities through at least 13 longest linear steps with 0.8% overall yield due to its complex structure such as fused hexacyclic core with 8 contiguous stereocenters. Therefore, structural simplification strategy is applied to pleurotin natural products for their structure-activity relationship (SAR) study and further therapeutics development. Herein, we judiciously designed pleurotin analogs of tricyclic A/D/E ring core, retaining the putative pharmacophore of para-quinone moiety D and its supportive A and E rings. Thus 16 simplified analogs of pleurotin bearing tricyclic A/D/E core were readily synthesized in only 2 to 6 steps with up to 50% overall yield from commercially available materials. Significantly, the best analog 14f with benzonitrile substituent exhibited more potent TrxR inhibitory activity with an IC₅₀ of 3.5 μM than the positive control micheliolide (IC₅₀ = 6.23 μM). Furthermore, the mechanism study revealed that compound 14f could induce apoptosis of tumor cells by inducing ROS generation and inhibiting TrxR activities. Our study for the first time showed that the tricyclic A/D/E ring scaffold from the natural product pleurotin (1) with proper substitution can maintain or even improve the TrxR inhibitory and antiproliferative activities, with high synthetic accessibility, affording natural product-derived lead compounds for the further development of TrxR inhibitors as anti-tumor therapeutics.