Djakonoviosides A, A1, A2, B1–B4 — Triterpene Monosulfated Tetra- and Pentaosides from the Sea Cucumber Cucumaria djakonovi: The First Finding of a Hemiketal Fragment in the Aglycones; Activity against Human Breast Cancer Cell Lines

Abstract

Seven new monosulfated triterpene glycosides, djakonoviosides A (1), A1 (2), A2 (3), and B1–B4 (4–7), along with three known glycosides found earlier in the other Cucumaria species, namely okhotoside A1-1, cucumarioside A0-1, and frondoside D, have been isolated from the far eastern sea cucumber Cucumaria djakonovi (Cucumariidae, Dendrochirotida). The structures were established on the basis of extensive analysis of 1D and 2D NMR spectra and confirmed by HR-ESI-MS data. The compounds of groups A and B differ from each other in their carbohydrate chains, namely monosulfated tetrasaccharide chains are inherent to group A and pentasaccharide chains with one sulfate group, branched by C-2 Qui2, are characteristic of group B. The aglycones of djakonoviosides A2 (3), B2 (5), and B4 (7) are characterized by a unique structural feature, a 23,16-hemiketal fragment found first in the sea cucumbers’ glycosides. The biosynthetic pathway of its formation is discussed. The set of aglycones of C. djakonovi glycosides was species specific because of the presence of new aglycones. At the same time, the finding in C. djakonovi of the known glycosides isolated earlier from the other species of Cucumaria, as well as the set of carbohydrate chains characteristic of the glycosides of all investigated representatives of the genus Cucumaria, demonstrated the significance of these glycosides as chemotaxonomic markers. The membranolytic actions of compounds 1–7 and known glycosides okhotoside A1-1, cucumarioside A0-1, and frondoside D, isolated from C. djakonovi against human cell lines, including erythrocytes and breast cancer cells (MCF-7, T-47D, and triple negative MDA-MB-231), as well as leukemia HL-60 and the embryonic kidney HEK-293 cell line, have been studied. Okhotoside A1-1 was the most active compound from the series because of the presence of a tetrasaccharide linear chain and holostane aglycone with a 7(8)-double bond and 16β-O-acetoxy group, cucumarioside A0-1, having the same aglycone, was slightly less active because of the presence of branching xylose residue at C-2 Qui2. Generally, the activity of the djakonoviosides of group A was higher than that of the djakonoviosides of group B containing the same aglycones, indicating the significance of a linear chain containing four monosaccharide residues for the demonstration of membranolytic action by the glycosides. All the compounds containing hemiketal fragments, djakonovioside A2 (3), B2 (5), and B4 (7), were almost inactive. The most aggressive triple-negative MDA-MB-231 breast cancer cell line was the most sensitive to the glycosides action when compared with the other cancer cells. Okhotoside A1-1 and cucumarioside A0-1 demonstrated promising effects against MDA-MB-231 cells, significantly inhibiting the migration, as well as the formation and growth, of colonies.

Sulfated Triterpene Glycosides from the Far Eastern Sea Cucumber Cucumaria djakonovi: Djakonoviosides C1, D1, E1, and F1; Cytotoxicity against Human Breast Cancer Cell Lines; Quantitative Structure–Activity Relationships

“…An additional direction of scientific interest in these metabolites, based on the use of them as chemotaxonomic markers, allows for defining the systematic position and resolving taxonomic issues by analysis of the structural features of glycosides. Particularly, on the one hand, the isolation of novel compounds from C. djakonovi corroborated the apartness of this species from other closely related Cucumaria species; on the other hand, the presence of the same compounds in different species of the genus Cucumaria confirmed the specificity of glycosides at the genus level [5,14]. The analysis of the structure-activity relationships of these metabolites shows the significance of the different parts of molecules for the demonstration of bioactivity and their influence on the mechanisms of action of glycosides [15].…”

“…All these broaden the fundamental knowledge about the chemical diversity of natural products in general and of triterpenoids and their derivatives in particular. Actually, each new research study of the glycosidic composition of previously uninvestigated species or reinvestigation of species that were previously studied, but using modern techniques and equipment, leads to the finding of novel compounds [4,5]. Fairly recently, the metabolomic studies of the glycosidic profiles of diverse species of holothuroids appeared, providing very useful data on the chemical diversity of glycosides, their distribution, and their content inside the different internal parts of animals, as well as their ecological signal functions [6][7][8][9][10].…”

“…The interest of researchers in glycosides has been increased by their diverse and unique biological activity, including anticancer activity against different types of tumors, and immunomodulatory properties [11][12][13]. Hence, some of these substances isolated from C. djakonovi demonstrated a promising action against human breast cancer cells, especially against the most aggressive triple-negative MDA-MB-231 cell line, suppressing cells' viability, inhibiting colony formation and growth, and inhibiting the migration of cells [5]. These data indicate that glycosides could be used in the target therapy of breast cancer.…”

Anticancer Activity of the Marine Triterpene Glycoside Cucumarioside A2-2 in Human Prostate Cancer Cells

“…The marine triterpene glycoside cucucmarioside A 2 -2 was isolated from the extract of sea cucumber Cucumaria japonica as previously reported [47]. The purity of cucucmarioside A 2 -2 was determined by 13 C NMR spectroscopy and ESI mass-spectrometry.…”

“…Of particular interest are the antitumor properties of these compounds. It has previously been described that holothurians' triterpene glycosides inhibit the proliferation of human tumor cells of various origins, including cervical and lung carcinoma, liver and stomach cancer, breast and ovarian cancer, malignant melanoma, and other types [9][10][11][12][13][14][15][16]. It is also known that triterpenoids (specifically triterpene saponins of plant origin) can effectively inhibit the division of tumor cells and suppress the growth of hormone-dependent tumors [17].…”