Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cells

Uche, FI; McCullagh, J; Claridge, T; Richardson, A; Li, W

Abstract

Our previous studies demonstrated that cycleanine, a macrocyclic bisbenzylisoquinoline (BBIQ) alkaloid, showed potent anti-ovarian cancer activity via apoptosis induction. Here, we synthesized two novel (aminoalkyl) cycleanine analogues (2 and 3) through a simple and efficient two-step reaction starting from cycleanine isolated from Triclisia subcordata Oliv. These analogues showed greater potency than the unmodified cycleanine in three human ovarian cancer cell lines. Both 2 and 3 induced apoptosis in ovarian cancer cells by activations of caspases 3/7, cleavage of PARP, increase in subG1 cell cycle phase and in the percentage of apoptotic cells. Further confocal fluorescence microscopy analysis confirmed the cellular uptake of alkaloids in ovarian cancer cells by using the unique (alkynyl)cycleanine (3) via click chemistry reaction. Our results suggest that cycleanine could be a hit compound for the future development in attacking ovarian cancer.

Citation

Uche, F., McCullagh, J., Claridge, T., Richardson, A., & Li, W. (2018). Synthesis of (aminoalkyl)cycleanine analogues: cytotoxicity, cellular uptake, and apoptosis induction in ovarian cancer cells. Bioorganic and Medicinal Chemistry Letters, 1652-1656. https://doi.org/10.1016/j.bmcl.2018.03.038

• Acceptance Date: Mar 15, 2018
• Publication Date: May 15, 2018
• Journal: Bioorganic and Medicinal Chemistry Letters
• Print ISSN: 0960-894X
• Publisher: Elsevier
• Pages: 1652-1656
• DOI: https://doi.org/10.1016/j.bmcl.2018.03.038
• Keywords: Cycleanine; Bisbenzylisoquinoline alkaloid; Ovarian cancer; Semi-synthesis; Cellular uptake; Apoptosis
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0960894X18302324