Total synthesis, structural, and biological evaluation of stylissatin A and related analogs

Shaheen, Farzana, Jabeen, Almas, Ashraf, Samreen, Nadeem-ul-Haque, Muhammad, Ali Shah, Zafar, Asad Ziaee, Muhammad, Dastagir, Nida and Ganesan, A. ORCID: https://orcid.org/0000-0003-4862-7999 (2016) Total synthesis, structural, and biological evaluation of stylissatin A and related analogs. Journal of Peptide Science, 22 (9). pp. 607-617. ISSN 1075-2617

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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-Phe7-Pro6 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 of 1b being an epimer of the natural product, we repeated the synthesis using d-allo-Ile in place of l-Ile and a different site for macrocyclization. The resulting product (d-allo-Ile2)-stylissatin A (1c) was also found to have the trans-Phe7-Pro6 peptide conformations like rotamer 1b. Applying the second route to the synthesis of stylissatin A itself, we obtained stylissatin A natural rotamer 1a accompanied by rotamer 1b as the major product. Rotamers 1a, 1b, and the epimer 1c were separable by HPLC, and 1a was found to match the natural product in structure and biological activity. Six related analogs 2–7 of stylissatin A were synthesized on Wang resin and characterized by spectral analysis. The natural product (1a), the rotamer (1b), and (d-allo-Ile2)-stylissatin A (1c) exhibited significant inhibition of NO.. Further investigations were focused on 1b, which also inhibited proliferation of T-cells and inflammatory cytokine IL-2 production. The analogs 2–7 weakly inhibited NO. production, but strongly inhibited IL-2 cytokine production compared with synthetic peptide 1b. All analogs inhibited the proliferation of T-cells, with analog 7 having the strongest effect. In the analogs, the Pro6 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.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Medicinal Chemistry (former - to 2017) Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Depositing User:	Pure Connector
Date Deposited:	24 Sep 2016 00:25
Last Modified:	22 Oct 2022 01:26
URI:	https://ueaeprints.uea.ac.uk/id/eprint/60040
DOI:	10.1002/psc.2909

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