A total synthesis of cyclodepsipeptide [Leu]6-aureobasidin K using combination of solid- and solution-phase

Abstract

AbK 1 was successfully synthesized using a combination of solid-and solution-phase that has a difference with the previous method applied for the synthesis of other aureobasidin analogues, [2S,3S-Hmp]-AbL 2. The linear precursor was prepared by using solid-phase method with Fmoc strategy, in which an ester bond was constructed on the resin. The cyclic product was obtained from a solution-phase reaction of the linear precursor using HATU reagent. The crude of the cyclic peptide was purified using a column chromatography technique to obtain [Leu] 6-AbK 1 with a percent yield of 5.31% that is higher compared to previous similar method for synthesis of [2S,3S-Hmp]-AbL 2. The purity level of cyclic product was analyzed using analytical RP-HPLC (tR = 6.49 min) and analysis of structure using 1 H-NMR.

Synthesis and anticancer evaluation of [d-Ala]-nocardiotide A

“…The synthesis of linear hexapeptide of [D-Ala]-nocardiotide A was accomplished by Fmoc chemistry in the solid-phase method while cyclization of the linear peptide was performed using the solution phase. 13 D-Alanine at the C-terminus and Ltryptophan at N-terminus as small and large amino acids, respectively, were used to provide advantage on the cyclization process 14 because the presence of D-Ala residue induced a more favourable conformation cyclization, as reported by Davies et al 12 The linear hexapeptide was prepared by the solid-phase peptide synthesis (SPPS) method using Fmoc chemistry (Fig. 2).…”

“…In addition, six alpha carbons were conrmed with chemical shis of 51.0, 60.5, 56.3, 57.8, 59.8, and 41.2 ppm. Finally, 1 H-and 13 C-NMR data between the synthetic [D-Ala]-nocardiotide A and the isolated nocardiotide A were compared (Table 1). The chemical shis of 13 C atoms of [D-Ala]-nocardiotide A and the isolated nocardiotide A showed chemical shi differences in the range of 0.1-0.7 ppm; however, the Cb of the Ala residue of [D-Ala]nocardiotide A appeared at 19.2 ppm, while the Cb of the Ala residue in the isolated nocardiotide A appeared at 18.05 ppm (Table 1).…”

“…The HR-TOF ESI mass spectrometry result of peptide 8 showed [M + H] + with m/z of 787.4507, which was consistent with the calculated [M + H] + ion peak at m/z 787.4514 for C 42 H 58 N 8 O 7 of compound 8. The structure of 8 was also conrmed using 1 H-NMR and 13 C-NMR (Table 1).…”

“…3D). The product was further characterized using 1 H-and 13 C-NMR spectroscopy (Table 1). The 1 H-NMR data of [D-Ala]-nocardiotide A 9 showed six alpha protons of the peptide with chemical shis of 3.67, 4.08, 4.23, 4.34, 4.17, and 4.60 ppm.…”

“…Then, the gradient was increased to 100% solvent B at 25.1 min followed by maintenance at 100% solvent B up to 30 min time point. Peptides were characterized using UV-vis spectroscopy (TECAN innite pro 200), mass spectrometry, and 1 H-(500 MHz) and 13 C-(125 MHz) nuclear magnetic resonance (NMR) spectroscopy (Bruker-Avance).…”