Pyrrolizines as Potential Anticancer Agents: Design, Synthesis, Caspase-3 activation and Micronucleus (MN) Induction.

BACKGROUND

For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized.

METHODS

Structures of the new compounds were confirmed by IR, H-NMR, C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method.

RESULT

Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC values were less than 5 µM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC values were less than 10 µM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC values less than 10 µM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds).

CONCLUSION

The obtained results encourage considering these three compounds as novel anticancer prototypes.