Toward the Synthesis of a Heterocyclic Analogue of Natural Cyclooligopeptide with Improved Bio-Properties

Abstract

Aims: The present investigation is targeted toward the synthesis of a novel analogue of a natural peptide of marine origin. Background: Marine sponges are enriched with bioactive secondary metabolites especially circular peptides. Heterocycles are established organic compounds with potential biological value. Taking into consideration the bio-properties of heterocycles and marine sponge-derived natural peptides, an effort was made for the synthesis of a heterocyclic analogue of a natural cyclopeptide. Objective : A heterocyclic analogue of a sponge-derived proline-containing cyclic peptide, rolloamide A, was synthesized by interaction of Boc-protected L-histidinyl-L-prolyl-L-valine and L-prolyl-L-leucyl-L-prolyl-L-isoleucine methyl ester and compared with synthetic rolloamide A with bioactivity against bacteria, fungi, and earthworms. Methods: The synthesis of cycloheptapeptide was accomplished employing the liquid phase method. The larger peptide segment was prepared by interaction of Boc-protected L-prolyl-L-leucine with L-prolyl-L-isoleucine methyl ester. Similarly, the tripeptide unit was synthesized from Boc-protected L-histidinyl-L-proline with L-valine ester. The linear heptapeptide segment (7) was cyclized by utilizing pentafluorophenyl (pfp) ester, and the structure was elucidated by elemental and spectral (IR, 1H/13C NMR, MS) analysis. The peptide was also screened for diverse bioactivities such as antibacterial, antifungal, and potential against earthworms and cytotoxicity. Results: The novel cyclooligopeptide was synthesized with 84% yield by making use of carbodiimides. The synthesized cyclopeptide exhibited significant cytotoxicity against two cell lines. In addition, promising antifungal and antihelmintic properties were observed for newly synthesized heterocyclic peptide derivative (8) against dermatophytes and three earthworm species at 6 µg/mL and 2 mg/mL, respectively. Conclusion: Solution-phase technique employing carbodiimide chemistry established to be promising for synthesizing the cycloheptapeptide derivative (8), and C5H5N was proved a better base for heptapeptide circling, when compared to N-methylmorpholine and triethylamine.