Synthesis and mechanisms of action of novel harmine derivatives as potential antitumor agents

Abstract

A series of novel harmine derivatives bearing a benzylindine substituent in position-1 of β-carboline ring were synthesized and evaluated as antitumor agents. The N2-benzylated β-carboline derivatives 3a–g represented the most interesting anticancer activities and compound 3c was found to be the most active agent to diverse cancer cell lines such as gastric carcinoma, melanoma and colorectal cancer. Notably, compound 3c showed low toxicity to normal cells. The treatment significantly induced cell apoptosis. Mechanistically, PI3K/AKT signaling pathway mediated compound 3c-induced apoptosis. Compound 3c inhibited phosphorylation of AKT and promoted the production of reactive oxygen species (ROS). The ROS scavenger, LNAC and GSH, could disturb the effect of compound 3c induced apoptosis and PI3K activity inhibitor LY294002 synergistically enhanced compound 3c efficacy. Moreover, the results from nude mice xenograft model showed that compound 3c treatment effectively inhibited tumor growth and decreased tumor weight. Collectively, our results demonstrated that compound 3c exerts apoptotic effect in cancer cells via suppression of phosphorylated AKT and evocation of ROS generation, which suggested that compound 3c might be served as a promising therapeutic agent for cancer treatment.

Suppression of Non-Small Cell Lung Cancer Growth and Metastasis by a Novel Small Molecular Activator of RECK

“…Harmine, a major constituent in a hallucinogenic botanical mixture ayahuasca and medical plant Peganum harmala , is a tricyclic compound belonging to the β-carboline alkaloids [22]. In latest studies, Harmine has been proved to inhibit the growth of ovarian cancer in vitro [23].…”

A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer

“…While harmine was not associated with overt toxicity in our in vivo model, harmine has been found to have potentially dose-limiting neurotoxicity in humans (25,44). Previous structure-activity studies have determined that harmine derivatives with substituents at position-2 and -9 can modulate the cytotoxic effects of harmine, while the addition of a bulky substituent at the -7 position can ameliorate the neurotoxicity associated with harmine (24–26,44).…”

“…Previous structure-activity studies have determined that harmine derivatives with substituents at position-2 and -9 can modulate the cytotoxic effects of harmine, while the addition of a bulky substituent at the -7 position can ameliorate the neurotoxicity associated with harmine (24–26,44). While micromolar range doses were required for harmine-mediated cytotoxicity in vitro , it should be noted that we were able to achieve doses in vivo that both inhibited tumor growth and promoted TWIST1 degradation without noticeable side effects.…”

A new potential anti‐cancer beta‐carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation

“…Harmine cannot be used as such for its anti‐cancer properties because of its neurotoxicity (Cao et al, ; Chen et al, ) but its scaffold is still of great interest for drug development. By example a N2‐benzylated β‐carboline derivative was recently shown to trigger apoptosis through PI3K/Akt inhibition and ROS production provoking thereby tumor growth inhibition in a colorectal cancer model in vivo (Zhang et al, ). In vitro, a series of trisubstituted compounds showed efficiency against a cervical cancer cell line and induced cell cycle arrest and apoptosis through inhibition of the polo‐like kinase 1, which participates in the cell cycle progression (Han et al, ).…”