Minutissamides A-D, antiproliferative cyclic decapeptides from the cultured cyanobacterium Anabaena minutissima

Abstract

Four cyclic decapeptides, minutissamides A-D (1-4), were isolated from the cultured cyanobacterium Anabaena minutissima (UTEX 1613). The planar structures were determined using various spectroscopic techniques including HRESIMS and 1D and 2D NMR experiments. The absolute configurations of the α-amino acid residues were assigned using Marfey's method after acid hydrolysis. The absolute configuration of a β-amino acid residue was assigned by a combination of the advanced Marfey's method, J-based configurational analysis, and ROE spectroscopic analysis. The structures of minutissamides A-D (1-4) were characterized by the presence of three nonstandard α-amino acid residues (two α,β-dehydro-α-aminobutyric acids and one N-methylated Asn) and one β-amino acid residue (2-hydroxy-3-amino-4-methyldodecanoic acid or 2-hydroxy-3-amino-4-methylhexadecanoic acid). Minutissamides A-D (1-4) exhibited antiproliferative activity against the HT-29 human colon cancer cell line with IC₅₀ values of 2.0, 20.0, 11.8, and 22.7 μM, respectively.

Figure 1

Key 2D correlations of minutissamide A (1) that were used for the determination of the planar structure of 1.

Figure 2

ESI-MS/MS fragmentation of minutissamide A (1).

Figure 3

Newman projections for (a) C-2/C-3 and (b) C-3/C-4. All possible relative conformations are shown. The DQF-COSY and phase-sensitive HMBC spectra were used for the calculation of homo- and hetero nuclear coupling constants. Labels below projections denote the predicted size of coupling constants. The predicted values that are consistent with observed values are highlighted by a box. Observed rOe correlations are presented as double-headed arrows: (a) H-2/H-4 and (b) H-2/H₂-5.

Chart 1