Total Synthesis of a Reversed-Bacicyclin Using a Combination of Solid- and Solution-Phase Methods

Rani Maharani; Anastasya Firdausi; Tri Mayanti; Desi Harneti; Nurlelasari Nurlelasari; Safri Ishmayana; Kindi Farabi; Unang Supratman; Ace Tatang Hidayat

doi:10.22146/ijc.72956

Total Synthesis of a Reversed-Bacicyclin Using a Combination of Solid- and Solution-Phase Methods

https://doi.org/10.22146/ijc.72956

Rani Maharani^(1*), Anastasya Firdausi⁽²⁾, Tri Mayanti⁽³⁾, Desi Harneti⁽⁴⁾, Nurlelasari Nurlelasari⁽⁵⁾, Safri Ishmayana⁽⁶⁾, Kindi Farabi⁽⁷⁾, Unang Supratman⁽⁸⁾, Ace Tatang Hidayat⁽⁹⁾

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Natural Product and Synthesis, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Natural Product and Synthesis, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Natural Product and Synthesis, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Natural Product and Synthesis, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(6) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(7) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Natural Product and Synthesis, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(8) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Natural Product and Synthesis, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(9) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Natural Product and Synthesis, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(*) Corresponding Author

Abstract

Bacicyclin is a cyclic hexapeptide with antibacterial activity against Enterococcus faecalis and Staphylococcus aureus with minimum inhibition concentration (MIC) values of 8 and 12 µM, respectively. Studies on a reversed sequence of bacicyclin were conducted to investigate how the reversed peptide sequence affects its biological properties. A reversed-bacicylin, cyclo-(Gly-Leu-Val-Ile-Ala-Phe), was successfully synthesized by constructing the linear precursor on 2-chlorotrityl chloride resin using a Fmoc-based strategy. The HATU/HOAt reagent was applied in all peptidic bond formations, and the desired linear hexapeptide (82% yield) was cleaved off the resin using a mixture of trifluoroacetic acid:dichloromethane (2:8). The linear peptide was cyclized using 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexa-fluorophosphate (HATU) as a coupling agent and diisopropylethylamine (DIPEA) as the base in a very dilute solution (0.001 M) in dichloromethane, then purified by octadecyl silica gel (ODS) column chromatography to obtain the reversed-bacicyclin (43.7% yield). The purity of the cyclic product was analyzed using analytical RP-HPLC (t_R = 20.01 min), and characterized by HR-TOF-MS, ¹H-NMR, and ¹³C-NMR. The biological activity of the reversed-bacicyclin is much lower compared to bacicyclin, indicating that the amino acid sequence of the cyclopeptide dictates the antibacterial activity. This finding gives additional information on the relationship between peptide sequence and biological properties.

Keywords

bacicyclin; solid-phase peptide synthesis; cyclisation; cyclic hexapeptide; antibacterial peptide

Full Text:

Full Text PDF Full Text PDF-Suppl. Data

References

[1] Ha, K., Monbaliu, J.C.M., Williams, B.C., Pillai, G.G., Ocampo, C.E., Zeller, M., Stevens, C.V., and Katritzky, A.R., 2012, A convenient synthesis of difficult medium-sized cyclic peptides by Staudinger mediated ring-closure, Org. Biomol. Chem., 10 (40), 8055–8058.

[2] Zhong, C., Liu, T., Gou, S., He, Y., Zhu, N., Zhu, Y., Wang, L., Liu, H., Zhang, Y., Yao, J., and Ni, J., 2019, Design and synthesis of new N-terminal fatty acid modified-antimicrobial peptide analogues with potent in vitro biological activity, Eur. J. Med. Chem., 182, 111636.

[3] Sawicka-Gutaj, N., Owecki, M., and Ruchala, M., 2018, Pasireotide-mechanism of action and clinical applications, Curr. Drug Metab., 19 (10), 876–882.

[4] Noh, H.J., Hwang, D., Lee, E.S., Hyun, J.W., Yi, P.H., Kim, G.S., Lee, S.E., Pang, C., Park, Y.J., Chung, K.H., Kim, G.D., and Kim, K.H., 2015, Anti-inflammatory activity of a new cyclic peptide, citrusin XI, isolated from the fruits of Citrus unshiu, J. Ethnopharmacol., 163, 106–112.

[5] Wiese, J., Abdelmohsen, U.R., Motiei, A., Humeida, U.H., and Imhoff, J.F., 2018, Bacicyclin, a new antibacterial cyclic hexapeptide from Bacillus sp. strain BC028 isolated from Mytilus edulis, Bioorg. Med. Chem. Lett., 28 (4), 558–561.

[6] Chen, Q., Wu, M., Chang, Q., and Zhao, X., 2021, Total synthesis and modification of Bacicyclin (1), a new marine antibacterial cyclic hexapeptide, Tetrahedron Lett., 63, 152705.

[7] Damjanovic, J., Miao, J., Huang, H., and Lin, Y.S., 2021, Elucidating solution structures of cyclic peptides using molecular dynamics simulations, Chem. Rev., 121 (4), 2292–2324.

[8] Jwad, R., Weissberger, D., and Hunter, L., 2020, Strategies for fine-tuning the conformations of cyclic peptides, Chem. Rev., 120 (17), 9743–9789.

[9] Claro, B., Peón, A., González-Freire, E., Goormaghtigh, E., Amorín, M., Granja, J.R., Garcia-Fandiño, R., and Bastos, M., 2021, Macromolecular assembly and membrane activity of antimicrobial D, L-α-Cyclic peptides, Colloids Surf., B, 112086.

[10] Farah, H.I., Supratman, U., Hidayat, A.T., and Maharani, R., 2022, An overview of the synthesis of biologically active cyclodepsipeptides, ChemistrySelect, 7 (1), e202103470.

[11] Malesevic, M., Strijowski, U., Bächle, D., and Sewald, N., 2004, An improved method for the solution cyclization of peptides under pseudo-high dilution conditions, J. Biotechnol., 112 (1-2), 73–77.

[12] Tsutsumi, L.S., Tan, G.T., and Sun, D., 2017, Solid-phase synthesis of cyclic hexapeptides wollamides A, B and desotamide B, Tetrahedron Lett., 58 (27), 2675–2680.

[13] Tsutsumi, L.S., Elmore, J.M., Dang, U.T., Wallace, M.J., Marreddy, R., Lee, R.B., Tan, G.T., Hurdle, J.G., Lee, R.E., and Sun, D., 2018, Solid-phase synthesis and antibacterial activity of cyclohexapeptide wollamide B analogs, ACS Comb. Sci., 20 (3), 172–185.

[14] Chen, Y.X., Liu, C., Liu, N., Wu, Y., Zhao, Q.J., Hu, H.G., Li, X., and Zou, Y., 2018, Total synthesis and antibacterial study of cyclohexapeptides desotamide B, wollamide B and their analogs, Chem. Biodivers., 15 (1), e1700414.

[15] Bodanszky, M., 2012, Principles of Peptide Synthesis, Springer Science & Business Media, Berlin, Germany.

[16] Mustafa, Y.F., Khalil, R.R., and Mohammed, E.T., 2020, Antimicrobial activity of aqueous extracts acquired from the seeds of two apples’ cultivars, Syst. Rev. Pharm., 11 (2), 382–387.

[17] Chan, W.C., and White, P., 1999, Fmoc Solid Phase Peptide Synthesis: A Practical Approach, Oxford University Press, Oxford, UK.

[18] Behrendt, R., White, P., and Offer, J., 2016, Advances in Fmoc solid‐phase peptide synthesis, J. Pept. Sci., 22 (1), 4–27.

[19] Ma, C., Chen, M., Chu, W., Tao, J., Kong, D., Zhang, M., and Feng, W., 2019, A practical and total synthesis of pasireotide: Synthesis of cyclic hexapeptide via a three-component condensation, Molecules, 24 (11), 2185.

[20] White, C.J., and Yudin, A.K., 2011, Contemporary strategies for peptide macrocyclization, Nat. Chem., 3 (7), 509–524.

[21] Humphrey, J.M., and Chamberlin, A.R., 1997, Chemical synthesis of natural product peptides: Coupling methods for the incorporation of noncoded amino acids into peptides, Chem. Rev., 97 (6), 2243–2266.

[22] Napitupulu, O.I., Sumiarsa, D., Subroto, T., Nurlelasari, N., Harneti, D., Supratman, U., and Maharani, R., 2019, Synthesis of cyclo-PLAI using a combination of solid-and solution-phase methods, Synth. Commun., 49 (2), 308–315.

[23] Kurnia, D.Y., Maharani, R., Hidayat, A.T., Al‐Anshori, J., Wiani, I., Mayanti, T., Harneti, D., and Supratman, U., 2021, Total synthesis of xylapeptide B [Cyclo‐(L‐Leu‐L‐Pro‐N‐Me‐Phe‐L‐Val‐D‐Ala)], J. Heterocycl. Chem., 59 (1), 131–136.

DOI: https://doi.org/10.22146/ijc.72956