Zephycandidine A and Synthetic Analogues—Synthesis and Evaluation of Biological Activity

A convenient total synthesis of the imidazo[1,2-f]phenanthridine-type Amaryllidaceae alkaloid zephycandidine A (<b>3</b>) was developed, which further allowed us to perform modifications of substituents on benzenoid ring A and imidazole ring D. The biological activities of all synthesized compounds were evaluated, and it was reported that activities against cancer cells of the parent alkaloid were poorly reproducible, while the closely related analogue THK-121 (<b>11</b>) showed a strong inhibitory effect on proliferation. Additionally, our novel analogue significantly induced cell death via the intrinsic apoptosis pathway, evident by the loss of mitochondrial membrane potential, increased mitochondrial oxidative stress, and disrupted mitochondrial structure in the same cells. At the same time, healthy cells were less affected by the treatment with THK-121 (<b>11</b>), indicating a potential therapeutic margin.