Synthesis and in vitro/in vivo anticancer evaluation of pentacyclic triterpenoid derivatives linked with l-phenylalanine or l-proline.

The newly synthesized glycine- l -phenylalanine conjugates 11 and 16 have good anticancer activity. In vivo and in vitro experiments showed that both compounds inhibit the growth of solid tumors by inducing apoptosis of cancer cells. [Display omitted] • 37 triterpenoid acid derivatives linked to l -phenylalanine or l -proline were synthesized. • Glycyrrhetinic acid (GA) derivatives 11 (IC 50 = 0.2 μM) and 16 (IC 50 = 0.7 μM) are much more potent than GA. • 11 and 16 showed significant tumor growth inhibition in A549 and T24 tumor xenograft model, respectively. • 16 showed low toxicity in vitro and in vivo experiments. • The mechanisms of action of compounds 11 and 16 were extensively investigated. Extensive research effort has been put in pentacyclic triterpenoids due to their numerous biological activities. However, their poor water solubility and low oral bioavailability limit their antitumor effects in vivo. To address these issues, 37 triterpenoid acid derivatives linked to l -phenylalanine or l -proline were designed and synthesized in this study. Structure-activity relationship (SAR) studies found two promising glycyrrhetinic acid (GA) derivatives 11 and 16. Compound 11 was obtained by C3-OH esterification and C30-COOH modification with l -phenylalanine while 16 was obtained by attaching C3-OH with l -phenylalanine. Compounds 11 and 16 exhibit up to 48- and 120-fold improvement respectively compared with the IC 50 values of naturally occurring GA in the cellular assay. Fluorescence microscope and flow cytometric analysis suggested that both compounds 11 and 16 increased the content of ROS and Ca2+ in cancer cells, decreased mitochondrial membrane potential (JC-1), and activated the regulator caspase-3/8/9 to trigger cell apoptosis. RNA-seq analysis and western blot analysis indicated that compounds 11 and 16 may promote apoptosis by upregulating the functions of pro-apoptotic factors while inhibiting the proteasome activity. [ABSTRACT FROM AUTHOR]