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

Abstract

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 µM, respectively compared to their Boc-protected analogs 2a (IC₅₀ 20 µM) and 3c (IC₅₀ 38.51 µM) and cyclic peptides 2 (>100 µM) and 3 (47 µM). These results were further validated by biological experiments such as colony formation and wound healing assays.

Graphical Abstract

Keywords:

• Anticancer activities
• cell migration efficiency
• cyclic peptides
• linear peptides
• Reniochalistatin

Acknowledgment

K.C.G. is thankful to CSIR, New Delhi for his fellowship. C.B. is grateful to DST-WOS A for her fellowship. P.B. thanks DBT-RA for financial support.

Additional information

Funding

S.S. thanks Indo-French Centre for promotion of advanced research (CEFIPRA) for financial support by a grant [IFC/A/5105-2/2014/1060].