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

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