Identification of quinazolinone and quinoline alkaloids from Peganum harmala L. inducing mitochondria-mediated apoptosis in liver cancer.

Two novel alkaloids, pegaharmolinones A and B (1-2), featuring an unprecedented 6/6/5/5 tetracyclic skeleton based on a 1,4-dihydro-6H-pyrrolo[2',3':3,4]pyrrolo[2,1-b]quinazolin-6-one core, and nineteen undescribed alkaloids, including luotonins G-L (3-7, 11) and pegaharmnolines A-K (18-22, 26, 29-30, 33-35), as well as fourteen known analogs, were isolated from the aerial parts of Peganum harmala. Their structures and absolute configurations were determined through analysis of NMR, HR-ESI-MS spectroscopic data, and ECD calculations, supported by a strategy of CASE-DFT. A plausible biosynthetic pathway for 1 and 2 was proposed. The anticancer activity in vitro was evaluated using the CCK-8 method, revealing that compound 22 exhibited potent efficacy and high selectivity, with an IC50 value of 6.49 μM and a selectivity index greater than 10. A series of bioassay suggested that 22 significantly suppressed the proliferation and migration of Hep G2 cells, and induced mitochondria-mediated apoptosis through both intrinsic and extrinsic pathways. Moreover, the SAR analysis of the tested active compounds provides structural modification strategies for the natural lead candidates 2 and 22.