Synthesis and Cytotoxic Activity of Several Novel N-Alkyl-Plinabulin Derivatives With Aryl Group Moieties

Seven novel N-alkyl--plinabulin derivatives with aryl groups moieties (nitroquinoline, 1,4-dihydroquinoline, 4-methoxybenzene, and 4-chlorobenzene) have been synthesized via aldol condensation and alkylation in one-pot, and tested for their cytotoxicity against 4 cancer cell lines (KB, HepG2, Lu, and MCF7). Compounds (Z)-3-((6,8-dimethyl-4-oxo-1,4-dihydroquinolin-2-yl) methylene)-6-((Z)-4-methoxybenzylidene)-1-(prop-2-yn-1-yl)piperazine-2,5-dione (5a), (Z)-6-((Z)-4-methoxybenzylidene)-1-(prop-2-yn-1-yl)-3-((1,6,8-trimethyl-4-oxo-1,4-dihydroquinolin-2-yl)methylene)piperazine-2,5-dione (5b), and (Z)-3-((Z)-4-chlorobenzylidene)-1,4-dimethyl-6-((8-methyl-4-nitroquinolin-2-yl)methylene)piperazine-2,5-dione (8) showed strong cytotoxicity against 3 of the cancer cells lines (KB, HepG2 and Lu) with IC50 values ranging from 3.04 to 10.62 mu M. The quinoline-derived compounds had higher cytotoxic activity than the benzaldehyde derivatives. The successful synthesis of these derivatives offers useful information for the development of more potent vascular disrupting agents based on plinabulin.