Synthesis and anticancer activities of proline-containing cyclic peptides and their linear analogs and congeners

A solution phase method was adopted for the synthesis of proline-containing cyclic pentapeptide 2 and total synthesis of naturally occurring cyclic heptapeptide Reniochalistatin B 3. For the synthesis of 3, both divergent and convergent strategies were used to improve the overall yield from 12 to 25%. Different N and C terminal modified linear analogs and congeners of 2 and 3 were synthesized. Both cyclic peptides 2 and 3 and their linear analogs/congeners were evaluated for anti-cancer activity against HeLa cell line, among which pentapeptide 2 h and hexapeptide 3n with N-terminal protected hexafluoroisopropyl carbamates (HFIPC) interestingly showed higher cytotoxicity with an IC50 of 2.73 and 4.3 mu M, respectively compared to their Boc-protected analogs 2a (IC50 20 mu M) and 3c (IC50 38.51 mu M) and cyclic peptides 2 (>100 mu M) and 3 (47 mu M). These results were further validated by biological experiments such as colony formation and wound healing assays. [GRAPHICS]