Antineoplastic Agents. 607. Emetine Auristatins

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Pharmacology

Background:

• Dolastatin 10 analogs, quinstatins and isoquinstatins, exhibit significant biological activity.
• Isoquinoline moieties are key components in various biologically active compounds.
• Emetine, an isoquinoline alkaloid, possesses notable pharmacological properties.

Purpose of the Study:

• To synthesize novel hybrid molecules combining the dolastatin 10 peptide sequence with the isoquinoline alkaloid emetine.
• To investigate the biological activity of these new peptide-emetine hybrids.
• To assess the impact of covalently bonding the dolastatin 10 peptide sequence to emetine on its activity.

Main Methods:

• Covalent bonding of the Dov-Val-Dil-Dap peptide sequence of dolastatin 10 to the N-2' secondary amine of emetine.
• Synthesis of three new hybrid molecules: compounds 5, 9, and 10.
• Comparative biological activity assessment of the synthesized hybrids against emetine.

Main Results:

• Complete retention of emetine's biological activity was observed in hybrid 5.
• Hybrids 9 and 10 exhibited a 10-fold decrease in biological activity compared to emetine.
• Unexpectedly, substitution at the N-2' position of emetine did not abolish activity in all cases.

Conclusions:

• The synthesized peptide-emetine hybrids demonstrate varied biological activity profiles.
• Hybrid 5 represents a successful conjugation strategy, maintaining the parent compound's activity.
• These findings challenge the general assumption that N-2' substitution significantly diminishes emetine's activity.