Novel centratherin derivatives: Molecular docking design, asymmetric synthesis, and antitumoral activity

Abstract

Centratherin is a sesquiterpene lactone that has the potential to inhibit target proteins for cancer therapy, such as the inflammatory mediator NF-κB. Indoles also exhibit antitumoral activity and can modulate the NF-κB signaling pathway. Here we describe a molecular-docking guided semi-synthesis of indole-containing centratherin derivatives. In silico studies indicated that these compounds have high affinity to NF-κB and do not present toxicity or carcinogenicity. Two enantiomeric series of indole-centratherin hybrids were synthesized in three steps with good yields and ee, employing an organocatalyzed Friedel-Crafts alkylation as a key step. The compounds were evaluated against human leukemia K562 cells and showed promising antitumoral activities with IC50 ranging from 0.49 to 7.83 μM.