Biomimetic semi-synthesis, structural optimization and anti-HIV activity of naturally scarce eupholathone-, lathyranone- and integerrimine-type Euphorbia diterpenoids

Constructing structural diverse compound libraries based on naturally scarce skeletons is a key challenge in natural product medicinal chemistry research. In this study, structural diversification of three classes of naturally scarce Euphorbia diterpenoids (including 5/7/7/4 eupholathones, 6/11/3 lathyranones, and 5/11 integerrimenes) was achieved via a biomimetic skeleton conversion strategy yielding a library of 72 rare Euphorbia diterpenoid analogues, that was investigated as potential inhibitors of HIV replication. The eupholathone type esters exhibited the most potent anti-HIV activity, emerging as a promising class of anti-HIV agents within the Euphorbia diterpenoids family. Analysis of the structure-activity relationship revealed that the hydroxyl group at C6 of the eupholathone scaffold is a critical position for enhancing anti-HIV potency, with aromatic esters on being particularly favorable. Specifically, the eupholathone ester 2t showed the best anti-HIV-1 activity, with an EC₅₀ of 1.51 μM and a selectivity index of more than 66.2, suggesting its potential as a candidate for further antiviral drug development.