Synthesis of Cylcotetrapeptides Analogues to Natural Products as Herbicides

Abstract

The synthesis of cyclotetrapeptides analogues of the natural productos tentoxin and versicotide D, was achieved in good yield by solid phase peptide synthesis (SPPS) of their linear precursors and solution phase cyclization. All the cyclopeptides and several open precursors were evaluated as herbicides. Five cyclopeptides and five lineal peptides showed a significant inhibition (> 70 %) of Rye grass seed’s radicle growth at 67 μg/mL. The evaluation at lower concentration (4-11 M), indicates two cyclopeptides analogs of tentoxin, which present one (N-Methyl-D-Phe), and two NMe -AA (N-Methyl-Ala and N-Methyl-Phe), respectively, as the most active of them showing remarkable phytotoxic activity. In two cases the open precursors are as active as their corresponding cyclopeptide. However, many linear peptides are inactive and their cyclization derivatives showed herbicidal activity. In addition, two cyclopeptide analogues of versicotide D, showed improved activity than the natural product. The results indicate that the peptide sequence, the amino acid stereochemistry and the presence of N-methyl group have important influence on the phytotoxic activity. Moreover, several compounds could be considered as lead candidates in the development of bioherbicides.