Antitumor activity of pyrrolizines and their Cu(II) complexes: Design, synthesis and cytotoxic screening with potential apoptosis-inducing activity.

Two novel series including Schiff bases of the pyrrolizine-5-carboxamides and their Cu(II) complexes were designed, synthesized and analysed using spectral and analytical techniques. The analytical results indicated the formation of the complexes in 1:1 or 1:2 (Metal:Ligand) ratio. The geometry around the Cu centers was confirmed to be tetrahedral or octahedral. The cytotoxic activity of the new compounds was evaluated using MCF-7 (human breast adenocarcinoma), A2780 (human ovary adenocarcinoma) and HT29 (human colon adenocarcinoma), in addition to MRC5 (normal human fetal lung fibroblast) cells using the MTT cytotoxicity assay. The Schiff base 12c and the Cu complex 13b were the most active in the two series with IC 50 values in the range of 0.14–2.54 μM against the three cell lines. Also, the Cu complex 13e showed excellent activity against HT29 with IC 50  = 0.05μM. 7-Cyano- N -(4-methoxyphenyl)-6-((3-phenylallylidene) amino)-2,3-dihydro-1 H -pyrrolizine-5-carboxamide (12c) showed high selectivity (6–13 folds) for cancerous cells over normal cells; and it induced marginal increases in the G1 and S phases of MCF-7 cells during cell cycle analysis, while compound 13b increased the MCF-7 Sub-G1 proapoptotic population, and blocked cells in the G2-M phase in a dose dependent manner. The annexin V apoptosis assay revealed the ability of compounds 12c and 13b to increase the early apoptotic MCF-7 cell populations two and three fold, respectively. Furthermore, these findings were supported by data showing that the two compounds ( 12c and 13b ) elicit cytotoxic activity. Taken together, the data presented in this study warrants further in vitro and in vivo investigations. [ABSTRACT FROM AUTHOR]