Structures and Bioactivities of Quadrangularisosides A, A1, B, B1, B2, C, C1, D, D1–D4, and E from the Sea Cucumber Colochirus quadrangularis: The First Discovery of the Glycosides, Sulfated by C-4 of the Terminal 3-O-Methylglucose Residue. Synergetic Effect on Colony Formation of Tumor HT-29 Cells of these Glycosides with Radioactive Irradiation

Abstract

Thirteen new mono-, di-, and trisulfated triterpene glycosides, quadrangularisosides A–D4 (1−13) have been isolated from the sea cucumber Colochirus quadrangularis, which was collected in Vietnamese waters. The structures of these glycosides were established by 2D NMR spectroscopy and HR-ESI (High Resolution Electrospray Ionization) mass spectrometry. The novel carbohydrate moieties of quadrangularisosides D–D4 (8−12), belonging to the group D, and quadrangularisoside E (13) contain three sulfate groups, with one of them occupying an unusual position—at C(4) of terminal 3-O-methylglucose residue. Quadrangularisosides A (1) and D3 (11) as well as quadrangularisosides A1 (2) and D4 (12) are characterized by the new aglycones having 25-hydroperoxyl or 24-hydroperoxyl groups in their side chains, respectively. The cytotoxic activities of compounds 1–13 against mouse neuroblastoma Neuro 2a, normal epithelial JB-6 cells, erythrocytes, and human colorectal adenocarcinoma HT-29 cells were studied. All the compounds were rather strong hemolytics. The structural features that most affect the bioactivity of the glycosides are the presence of hydroperoxy groups in the side chains and the quantity of sulfate groups. The membranolytic activity of monosulfated quadrangularisosides of group A (1, 2) against Neuro 2a, JB-6 cells, and erythrocytes was relatively weak due to the availability of the hydroperoxyl group, whereas trisulfated quadrangularisosides D3 (11) and D4 (12) with the same aglycones as 1, 2 were the least active compounds in the series due to the combination of these two structural peculiarities. The erythrocytes were more sensitive to the action of the glycosides than Neuro 2a or JB-6 cells, but the structure–activity relationships observed for glycosides 1–13 were similar in the three cell lines investigated. The compounds 3−5, 8, and 9 effectively suppressed the cell viability of HT-29 cells. Quadrangularisosides A1 (2), C (6), C1 (7), and E (13) possessed strong inhibitory activity on colony formation in HT-29 cells. Due to the synergic effects of these glycosides (0.02 μM) and radioactive irradiation (1 Gy), a decreasing of number of colonies was detected. Glycosides 1, 3, and 9 enhanced the effect of radiation by about 30%.

Structure-Activity Relationships of Holothuroid’s Triterpene Glycosides and Some In Silico Insights Obtained by Molecular Dynamics Study on the Mechanisms of Their Membranolytic Action

“…Analyzing the majority of tested compounds, it has been revealed that the membranes of erythrocytes are more sensitive to the glycoside membranolytic action than the other tested cells such as mouse spleen lymphocytes, ascites of mouse Ehrlich carcinoma, and neuroblastoma Neuro 2a or normal epithelial JB-6 cells. This regularity was observed in the glycosides of the Actinocucumis typica [23], Colochirus robustus [24], Massinium magnum [25,26], Eupentacta fraudatrix [27][28][29], Psolus fabricii [30,31], and Colochirus quadrangularis [32] sea cucumbers. One of the explanations for this phenomenon may be the enrichment of red blood cell membranes with cholesterol [10].…”

“…It became obvious that glycosides cytotoxic activity depends structures, but also on the type of processed cells differing by compo peculiarities of their membranes [1]. Analyzing the majority of tested been revealed that the membranes of erythrocytes are more sensit membranolytic action than the other tested cells such as mouse spleen of mouse Ehrlich carcinoma, and neuroblastoma Neuro 2a or normal This regularity was observed in the glycosides of the Actinocucumis t robustus [24], Massinium magnum [25,26], Eupentacta fraudatrix [27][28][29], and Colochirus quadrangularis [32] sea cucumbers. One of the ex phenomenon may be the enrichment of red blood cell membranes with…”

“…The analysis of SAR in the raw of glycosides from the sea cucumbers Colochirus quadrangularis [32] (quadrangularisosides B 2 (33), D 2 (34), and E (35)), C. robustus [24] (colochiroside C ( 36)) (Figure 6) and P. fabricii [30] (psolusosides A ( 16), E (17) (Figure 3), and F ( 37)) (Figure 6) with the same holostane aglycone and linear tetrasaccharide chains and differing by the third monosaccharide residue and the number and positions of sulfate groups, showed that they all were strong hemolytics (Table 1). However, the presence of a sulfate group at C-4 or C-6 of terminal MeGlc residue resulted in approximately a tenfold decrease in activity, while the sulfation of C-3 Qui2 or C-6 Glc3 did not decrease the hemolytic action.…”

“…Recently, the glycosides containing hydroperoxyl groups in the aglycone side chains were found in sea cucumbers C. quadrangularis (quadrangularisosides A (55) and A 1 (56) [32]) and P. fabricii (psolusoside D 3 (57) [44]) (Figure 13). The comparative analysis of their hemolytic activity with that of their structural analogs that contained hydroxyl groups in the same positions (colochirosides B 2 (38), B 1 (50), and psolusoside D 5 (58), correspondingly) showed that the influence of OOH-functionalities was not so negative (Table 1).…”

Echinoderms Metabolites: Structure, Functions, and Biomedical Perspectives

“…Quadrangularisosides A 1 , C, C 1 , and E possessed strong inhibitory activity on colony formation in HT-29 cells. Due to the synergic effects of these glycosides (0.02 µM) and radioactive irradiation (1 Gy), a decreasing number of colonies was detected [18]. The second article concerns the isolation and structural elucidation of six new monosulfated triterpene tetra-, penta-and hexa-osides, namely, kurilosides A 1 , A 2 , C 1 , D, E, and F, as well as the known earlier kuriloside A, with unusual non-holostane aglycones without lactone, from the sea cucumber Thyonidium (= Duasmodactyla) kurilensis (Levin) (Cucumariidae, Dendrochirotida), collected in the Sea of Okhotsk near Onekotan Island from a depth of 100 m. Structures of the glycosides were elucidated by 2D NMR spectroscopy and HR-ESI mass spectrometry.…”