Design, Synthesis, and Anticancer Evaluation of Novel 6-Alkynylated Harmine Derivatives

In order to explore the effect of alkynyl introduction at the 6-position of harmine on the antitumor activity, 23 novel 6-alkynylated harmine derivatives (3a-3w) were synthesized and investigated for their anti-proliferative activity on a panel of cancer cell lines. Compound 3u demonstrated the most potent anti-proliferative activity, with IC₅₀ = 0.77 µM against MDA-MB-231 cell lines. Further mechanistic investigations revealed that compound 3u could induce apoptosis in a concentration-dependent manner and arrest the cell cycle in the G2/M phase in MDA-MB-231 cells. In addition, compound 3u significantly suppressed cell migration in the wound healing assay and reduced the mitochondrial membrane potential of MDA-MB-231 cell lines. Furthermore, molecular docking studies revealed that compound 3u exhibited strong binding affinity to the active site of EGFR through hydrogen bonding and hydrophobic interaction. Moreover, the cytotoxic study of compound 3u on the BEAS-2B, a normal human lung epithelial cell line, further highlights the potential of compound 3u molecule as an anticancer agent for breast cancer with a selectivity index of 45.70.