In Vitro Cytotoxic Evaluation of New indolo-Triterpene Derivatives, Synthesized from Serjanic Acid

Pentacyclic triterpenes represent a very promising and expansive platform for bioactive natural products. Its potential has begun to be exploited by the pharmaceutical industry. The study of these secondary metabolites has been focused mainly in evaluating their activity as potential anti-viral and anti-cancer agents, and in most cases, the increase of the activity is closely related to the chemical modification of the hydroxyl or carboxyl group located at positions C-3 and/or C-28 of the molecule. At present, most of the research on the chemical modification of triterpenes involves the insertion of heterocyclic rings, either through covalent bonds or by ring fusion. 

Serjanic acid (1) is a natural pentacyclic triterpene found in the fruits of the plant Phytolacca icosandra (Phytolaccaceae). Despite the structural similarities of this compound with other bioactive triterpenes such as oleanolic, boswellic and moronic acids, there are almost no studies on the chemical modification of this acid. Due to this, and based on the biological and pharmacological potential that this compounds might have, in this study we carried out the synthesis, structural characterization and cytotoxic evaluation of six new indolo-triterpene derivatives (8 – 13) from the natural triterpenoid serjanic acid (1). The compounds were synthesized via indolization reactions between the ketones 2 and phenylhydrazines 3 – 7 and their structures elucidated by IR, ¹H-NMR, ¹³C-NMR and HR-MS techniques as: indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (8), 5-bromoindolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (9), 7-bromo-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (10), 4-bromo-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (11), 6-bromo-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (12) and 4,7-dichloro-indolo[2,3-b]olean-12-en-28,30-dioic acid-30-methyl ester (13). All compounds were tested trough the brine shrimp lethality assay to determinate their potential as cytotoxic agents. LC₅₀ values of the new synthesized compounds were between 28.6 and 78.8 micromolar.