First report on the synthesis and structural studies of trans-Phakellistatin 18: a rotamer of marine natural product phakellistatin 18

Abstract

Phakellistatin peptides from marine organisms are the sources of proline-rich cyclic peptides with reported significant antitumor activities. Phakellistatin 18 (1), reported from marine sponge Phakellia fusca, contains three proline-peptide linkages in cis form. We attempted the total synthesis of natural product 1 through solution-phase macrocyclization approach, as a result, the synthetic cyclic peptide 2 was obtained as a rotamer of natural product having all three proline residues in trans-conformation. Here, we describe the synthesis, structural, and cytotoxicity studies of trans-Phakellistatin 18 (2), and its analog [Ala^1,3,6]-Phakellistatin 18 (3). Detailed NMR studies were carried out to characterize the synthesized peptides, and anti-cancer screening was performed by using MTT assay. The synthetic trans-Phakellistatin 18 (2) (IC₅₀=67.5 ± 2.938 µM) showed comparable cytotoxicity against HepG2 cancer cell line with standard drug doxorubicin (IC₅₀=63.88 ± 6.48 µM). Here, the first synthetic and structural studies on trans-Phakellistatin 18 (2), and its anticancer screening against HepG2 cell line was reported.

Graphical Abstract

Keywords:

• Phakellistatin 18
• Phakellia fusca; HepG2 cell line
• proline-rich cyclopeptide

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Authors acknowledge the financial support from Higher Education Commission, Pakistan. This work was supported by a grants 5738/Sindh/NRPU/R&D/HEC/2016 and 8169/Sindh/NRPU/R&D/HEC/2017 from the Higher Education Commission, Pakistan.