Medicinal Chemistry Research

, Volume 28, Issue 5, pp 768–777 | Cite as

Synthesis and antitumor activity of cyclic octapeptide, samoamide A, and its derivatives

  • Fei Ge
  • Chi Zhang
  • Longbao Zhu
  • Wanzhen Li
  • Ping Song
  • Yugui TaoEmail author
  • Guocheng DuEmail author
Original Research


Using 2-chloro-trityl chloride resin as a solid phase carrier, a linear peptide was synthesized by Fmoc solid phase synthesis followed by liquid phase cyclization. After separation and purification by high-performance liquid chromatography (HPLC), cyclic octapeptide samoamide A was prepared. The synthesis yield was 54.5%. The structure of cyclic octapeptide samoamide A was characterized by electrospray ionization–mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR) spectrometry. The biological activity was evaluated by the CCK-8 assay and DPP4 enzyme activity inhibition assay. This compound exhibited high antitumor activity. Using samoamide A as a lead compound, eight cyclic octapeptide samoamide A derivatives (a, b, c, d, e, f, g, and h) were designed and synthesized using the alanine scanning method. The molecular weight and chemical structure of these derivatives were verified by ESI-MS and NMR, and the antitumor activity of the derivatives was analyzed. The antitumor activity of compound f was similar to that of samoamide A, and its replacement site is the non-active site of samoamide A, providing a theoretical basis for further modification and transformation of samoamide A.


Samoamide A Samoamide A derivatives Solid phase synthesis Alanine scanning method Antitumor activity Non-active site 



This work was supported by the National Natural Science Foundation of China (NSFC) [grant number 31671797], Natural Science Foundation of Anhui University [grant number KJ2017A123, KJ2018A0117 and KZ00217058], Anhui Province Major Scientific and Technological Projects [grant number17030701014], Anhui Natural Science Foundation [grant number1808085QC85], and the Youth Talent Support Program of Anhui Polytechnic University [grant number 2016BJRRC006].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

All authors listed have contributed to the conception, design, gathering, analysis or interpretation of data and have contributed to the writing and intellectual content of the article. All authors gave informed consent to the submission of this manuscript.

Supplementary material

44_2019_2333_MOESM1_ESM.docx (6.8 mb)
Supplementary Information


  1. Abdalla MA (2016) Medicinal significance of naturally occurring cyclotetrapeptides. J Nat Med 70:708–720CrossRefGoogle Scholar
  2. Al-Benna S, Shai Y, Jacobsen F, Steinstraesser L (2011) Oncolytic activities of host defense peptides. Int J Mol Sci 12:8027–8051CrossRefGoogle Scholar
  3. Andrade SN, Evangelista FCG, Seckler D, Marques DR, Freitas TR, Nunes RR, Oliveira JT, RIMA Ribeiro, Santos HB, Thome RG, Taranto AG, Santos FV, GHR Viana, Freitas RP, Humberto JL, Sabino AD, Hilario FF, Varotti FP (2018) Synthesis, cytotoxic activity, and mode of action of new Santacruzamate A analogs. Med Chem Res 11-12:2397–2413CrossRefGoogle Scholar
  4. Aneiros A, Garateix A (2004) Bioactive peptides from marine sources: pharmacological properties and isolation procedures. J Chromatogr B 803:41–53CrossRefGoogle Scholar
  5. Chang Q, Li YL, Zhao X (2018) Total synthesis and cyclization strategy of samoamide A, a cytotoxic cyclic octapeptide rich in proline and phenlalanine isolated from marine cyanobacterium. J Asian Nat Prod Res
  6. Dartois V, Sanchez-Quesada J, Cabezas E, Chi E, Dubbelde C, Dunn C, Granja J, Gritzen C, Weinberger D, Ghadiri MR, Parr TRJ (2005) Systemic antibacterial activity of novel synthetic cyclic peptides. Antimicrob Agents Ch49:3302–3310CrossRefGoogle Scholar
  7. Gogineni V, Hamann MT (2018) Marine natural product peptides with therapeutic potential: chemistry, biosynthesis, and pharmacology. Bba-Gen Subj 1862:81–196CrossRefGoogle Scholar
  8. Hu J, Cheng T, Zhang L, Sun B, Deng L, Xu H (2015) Anti-tumor peptide AP25 decreases cyclin D1 expression and inhibits MGC-803 proliferation via phospho-extracellular signal-regulated kinase-, Src-, c-Jun N-terminal kinase- and phosphoinositide 3-kinase-associated pathways. Mol Med Rep 12:4396–4402CrossRefGoogle Scholar
  9. Johnstone KD, Dieckelmann M, Jennings MP, Toth I, Blanchfield JT (2005) Chemo-enzymatic synthesis of a trisaccharide-linked peptide aimed at improved drug-delivery. Curr Drug Deliv 2:215–222CrossRefGoogle Scholar
  10. Khalily MP, Gerekci S, Gulec EA, Ozen C, Ozcubukcu S (2018) Structure-based design, synthesis and anticancer effect of cyclic Smac-polyarginine peptides. Amino Acids 50:1607–1616CrossRefGoogle Scholar
  11. Li CY, Gao N, Xue QQ, Ma N, Hu YQ, Zhang JF, Chen BL, Hou YC (2017) Screening and identification of a specific peptide binding to cervical cancer cells from a phage-displayed peptide library. Biotechnol Lett 39:1463–1469CrossRefGoogle Scholar
  12. Lim SS, Yoon SP, Park Y, Zhu WL, Park IS, Hahm KS, Shin SY (2006) Mechanism of antibacterial action of a synthetic peptide with an Ala-peptoid residue based on the scorpion-derived antimicrobial peptide IsCT. Biotechnol Lett 28:1431–1437CrossRefGoogle Scholar
  13. Li YZ, Zhao P, Zhan XP, Liu ZL, Mao ZM (2015) Synthesis and cytotoxic activities of novel amino acid-conjugates of pyrrole derivatives. Chin J Org Chem 35:167–174CrossRefGoogle Scholar
  14. Martin-Algarra S, Espinosa E, Rubio J, Lopez L, Juan J, Manzano JL, Carrion LA, Plazaola A, Tanovic A, Paz-Ares L (2009) Phase II study of weekly Kahalalide F in patients with advanced malignant melanoma. Eur J Cancer Prev 45:732–735CrossRefGoogle Scholar
  15. Mccusker CF, Kocienski PJ, Boyle FT, Schatzlein AG (2002) Solid-phase synthesis of c(RGDfK) derivatives: on-resin cyclisation and lysine functionalisation. Bioorg Med Chem Lett 12:547–549CrossRefGoogle Scholar
  16. Miyake T, Loch CM, Li R (2002) Identification of a multifunctional domain in autonomously replicating sequence-binding factor 1 required for transcriptional activation, DNA replication, and gene silencing. Mol Cell Biol 22:505–516CrossRefGoogle Scholar
  17. Naman CB, Rattan R, Nikoulina SE, Lee J, Miller BW, Moss NA, Armstrong L, Boudreau PD, Debonsi HM, Valeriote FA (2017) Integrating molecular networking and biological assays to target the isolation of a cytotoxiccyclic octapeptide, samoamide A, from an American Samoan Marine Cyanobacterium. J Nat Prod 80:625–633CrossRefGoogle Scholar
  18. Oudart JB, Brassart-Pasco S, Vautrin A, Sellier C, Machado C, Dupont-Deshorgue A, Brassart B, Baud S, Dauchez M, Monboisse JC, Harakat D, Maquart FX, Ramont L (2015) Plasmin releases the anti-tumor peptide from the NC1 domain of collagen XIX. Oncotarget 6:3656–3668CrossRefGoogle Scholar
  19. Riahi N, Liberelle B, Henry O, De Crescenzo G (2017) Impact of RGD amount in dextran-based hydrogels for cell delivery. Carbohyd Polym 161:219–227CrossRefGoogle Scholar
  20. Riely GJ, Gadgeel S, Rothman I, Saidman B, Sabbath K, Feit K, Kris MG, Rizvi NA (2007) A phase 2 study of TZT-1027, administered weekly to patients with advanced non-small cell lung cancer following treatment with platinum-based chemotherapy. Lung Cancer 55:181–185CrossRefGoogle Scholar
  21. Rosca EV, Koskimaki JE, Rivera CG, Pandey NB, Tamiz AP, Popel AS (2011) Anti-angiogenic peptides for cancer therapeutics. Curr Pharm Biotechno 12:1101–1116CrossRefGoogle Scholar
  22. Schubert M, Labudde D, Oschkinat H, Schmieder P (2002) A software tool for the prediction of Xaa-Pro peptide bond conformations in proteins based on 13C chemical shift statistics. J Biomol NMR 24:149–154CrossRefGoogle Scholar
  23. Valeriote FA, Tenney K, Media J, Pietraszkiewicz H, Edelstein M, Johnson TA, Amagata T, Crews P (2012) Discovery and development of anticancer agents from marine sponges: perspectives based on a chemistry-experimental therapeutics collaborative program. J Exp Ther Oncol 10:119–134Google Scholar
  24. Yi X, Yang K, Liang C, Zhong XY, Ning P, Song GS, Wang DL, Ge CC, Chen CY, Chai ZF, Liu Z (2015) Imaging-guided combined photothermal and radiotherapy to treat subcutaneous and metastatic tumors using Iodine-131-doped copper sulfide nanoparticles. Adv Funct Mater 25:4689–4699CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Biochemical EngineeringAnhui Polytechnic UniversityWuhuP. R. China
  2. 2.Key Laboratory of Industrial Biotechnology, Ministry of Education, School of BiotechnologyJiangnan UniversityWuxiP. R. China

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