Antineoplastic Agents. 607. Emetine Auristatins

The remarkable biological activity of the dolastatin 10 structural modifications quinstatins and isoquinstatins prompted further investigation into drug hybrids containing biologically active isoquinoline moieties. In this study, the isoquinoline alkaloid emetine was selected as one of the structural domains of a hybrid molecule. That was accomplished by covalently bonding the Dov-Val-Dil-Dap peptide sequence of dolastatin 10 peptide at the N-2' secondary amine of emetine. Three new hybrids were synthesized, 5, 9, and 10. Comparison of the biological activity of these new peptide-emetine analogues with emetine showed complete retention of activity for 5 and a 10-fold decrease for hybrids 9 and 10. The result was surprising, as the activity of emetine is usually lost or greatly reduced when substituted at the N-2' position.