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

doi:10.1016/j.bmcl.2018.03.038

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

Authors

FI Uche

J McCullagh

T Claridge

Alan Richardson a.richardson1@keele.ac.uk

Wenwu Li w.li@keele.ac.uk

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.

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