Precursor-Directed Synthesis of Apoptosis-Initiating N-Hydroxyalkyl Phenylbenzoisoquinolindione Alkaloids.

A precursor-directed approach to access N-hydroxyalkyl phenylbenzoisoquinolindiones (PBIQs) has been developed. Incubation of plant material of Xiphidium caeruleum with hydroxylamines of various chain lengths (C 2 , C 4 , C 6 , C 8 , C 10 and C 12 ) resulted in 11 new 5-hydroxy- and 5-methoxy PBIQs with different N-hydroxyalkyl side chain lengths. The antiproliferative effect and the cytotoxicity against HUVEC, K-562, and HeLa cell lines of 26 previously reported PBIQs and the 11 newly synthesized N-hydroxyalkyl PBIQs was determined for the first time. The results revealed that introducing long-chain N-aliphatic amine moieties improved the antiproliferative effect and cytotoxicity of PBIQs when compared to derivatives with N-amino acids as side chains.