(−)-Neocaryachine an Antiproliferative Pavine Alkaloid from Cryptocarya laevigata Induces DNA Double-Strand Breaks

摘要

Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH2Cl2 extract of Cryptocarya laevigata (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multidrug-resistant subline. Since more common 2,3,8,9-tetrasubstituted pavine alkaloids, such as crychine (>3), exhibit very mild or no cytotoxicity, this compound type has not been well investigated for antitumor activity. Thus, this report is the first discovery of a 7-hydroxylated pavine alkaloid, (−)-neocaryachine (>1), to demonstrate strong antiproliferative activity, with IC50 values of 0.06 to 0.41 µM against five tested tumor cell lines, including an MDR subline. Further mechanism of action studies revealed that >1 impacts the cellular S-phase by inducing DNA double-strand breaks.