Total synthesis, structural, and biological evaluation of stylissatin A and related analogs. (September 2016)

• Record Type: Journal Article
• Authors: Shaheen, Farzana; Jabeen, Almas; Ashraf, Samreen; Nadeem‐ul‐Haque, Muhammad; Shah, Zafar Ali; Ziaee, Muhammad Asad; Dastagir, Nida; Ganesan, A.
• Is Part Of: Journal of peptide science. Volume 22:Number 9(2016:Sep.)
• Page Start: 607
• Page End: 617
• Publication Date: 2016-09
• Subjects: solid‐phase peptide synthesis -- cyclic peptides -- proline rotamers -- inflammation -- nitric oxide -- interleukin 2 -- reactive oxygen species; Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.2909
• Languages: English
• ISSNs: 1075-2617

Abstract

Abstract : The natural product cyclic peptide stylissatin A (1a ) was reported to inhibit nitric oxide production in LPS‐stimulated murine macrophage RAW 264.7 cells. In the current study, solid‐phase total synthesis of stylissatin A was performed by using a safety‐catch linker and yielded the peptide with a trans ‐Phe 7 ‐Pro 6 linkage, whereas the natural product is the cis rotamer at this position as evidenced by a marked difference in NMR chemical shifts. In order to preclude the possibility of1b being an epimer of the natural product, we repeated the synthesis usingd ‐ allo ‐Ile in place ofl ‐Ile and a different site for macrocyclization. The resulting product (d ‐ allo ‐Ile 2 )‐stylissatin A (1c ) was also found to have the trans ‐Phe 7 ‐Pro 6 peptide conformations like rotamer1b . Applying the second route to the synthesis of stylissatin A itself, we obtained stylissatin A natural rotamer1a accompanied by rotamer1b as the major product. Rotamers1a, 1b, and the epimer1c were separable by HPLC, and1a was found to match the natural product in structure and biological activity. Six related analogs2–7 of stylissatin A were synthesized on Wang resin and characterized by spectral analysis. The natural product (1a ), the rotamer (1b ), and (d ‐ allo ‐Ile 2 )‐stylissatin A (1c ) exhibited significant inhibition of NO . . Further investigations were focused on1b, which also inhibited proliferation of T‐cells and inflammatory cytokine IL‐2 production. The analogs2–7 weakly inhibited NO . production, but strongly inhibited IL‐2 cytokine production compared with synthetic peptide1b . All analogs inhibited the proliferation of T‐cells, with analog7 having the strongest effect. In the analogs, the Pro 6 residue was replaced by Glu/Ala, and the SAR indicates that the nature of this residue plays a role in the biological function of these peptides. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Abstract : We report here the solid‐phase synthesis, structural studies, and biological evaluation of cyclic peptides stylissatin A, proline rotamer of stylissatin A, (D‐ allo ‐Ile 2 )‐stylissatin A, and six analogues of stylissatin A. The position of macrocyclization was found to influence the proline rotamer population of synthetic sytlissatin A. The synthetic stylissatin A, its epimer and trans, trans rotamer potently inhibited the NO . production. Related analogues of stylissatin A were identified as more potent inhibitors of interleukin 2 release.