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

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 ) (IC 50 =67.5 ± 2.938 µM) showed comparable cytotoxicity against HepG2 cancer cell line with standard drug doxorubicin (IC 50 =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.