Synthesis and cytotoxic evaluation of four new 6E-hydroximinosteroids.

Four new 6E-hydroximinosteroids (1, 2a, 3 and 4) have been synthesized from the corresponding ketones, 2ß,3ß-dihydroxy-5α-cholestan-6-one (5), 2α,3α-dihydroxy-5α-cholestan-6-one (6), 2ß,3α-dihydroxy-5α-cholestan-6-one (7) and 2ß,3α-dihydroxy-5α-cholestan-6-one-disulfate (8). The cytotoxic activity of the steroidal oximes was evaluated against two prostate carcinoma cell lines (PC-3 and LNCaP) and compared with that of five polyhydroxylated sulfated analogs (8-12). Oxime 3 and trisulfated analog 11 were the most active compounds with IC50 values of 10.8µM (PC-3) and 7.9µM (LNCaP), respectively.

Pseudocnoside A, a new cytotoxic and antiproliferative triterpene glycoside from the sea cucumber Pseudocnus dubiosus leoninus.

A new triterpene glycoside, pseudocnoside A (1), was isolated from the sea cucumber Pseudocnus dubiosus leoninus. The structure of the new compound was established on the basis of extensive NMR spectroscopic analysis ((1)H and (13)C NMR, (1)H,(1)H-COSY, HMBC, HSQC, TOCSY and NOESY), HR-ESI-MS data and chemical transformations. In addition, the cytotoxicity and antiproliferative activities of 1 and structurally related triterpene glycosides isolated from the sea cucumbers Psolus patagonicus and Hemioedema spectabilis were evaluated against cancer cell lines A-549 and HeLa.

A natural tetranortriterpenoid with immunomodulating properties as a potential anti-HSV agent.

Meliacine (MA), an antiviral principle present in partially purified leaf extracts of Melia azedarach L., prevents the development of herpetic stromal keratitis (HSK) in mice by diminishing the viral load in the eye and the severity of lesions caused by a virus-induced immunopathological reaction. The tetranortriterpenoid 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), obtained from MA purification, displays anti-herpetic activity and impedes nuclear factor kappaB (NF-kappaB) activation in HSV-1 infected conjunctival cells. To extend our understanding about CDM biological properties, we investigated its anti-HSV-1 activity as well as the effect on NF-kappaB activation and cytokine secretion induced by viral (HSV-1) and no-viral (LPS) stimuli, in corneal cells and macrophages. CDM exerted a potent anti-HSV-1 effect on corneal cells and inhibited NF-kappaB translocation to the nucleus, leading to a decrease in IL-6 production. Besides, CDM seemed to modulate IL-6 and TNF-alpha responses in macrophages, whether they were infected with HSV-1 or stimulated with LPS. However, CDM did not affect NF-kappaB activation in these cells, suggesting that an alternative NF-kappaB cell signaling pathway would be involved in the modulation of cytokine production. We conclude that, in addition to its antiviral effect, CDM would be acting as an immunomodulating compound which would be responsible for the improvement of murine HSK already reported.

Antiproliferative, cytotoxic and hemolytic activities of a triterpene glycoside from Psolus patagonicus and its desulfated analog.

BACKGROUND: The major triterpene glycoside of the sea cucumber Psolus patagonicus and its desulfated analog were tested for their antiproliferative, cytotoxic and hemolytic activities, and their effect on NF-kappaB activation. METHODS: The antiproliferative action of glycosides 1 and 2 were determined on 3 tumor cell lines. Their effect on the activation of NF-kappaB was evaluated by indirect immunofluorescence assay staining and the concomitant IkappaBalpha degradation was studied by Western blot. RESULTS: Both compounds were able to suppress the growth of 3 tumor cell lines (Hep3B, MDA-MB231 and A549) and induced the activation of NF-kappaB, a key player linking chronic inflammation and cancer, concomitant with IkappaBalpha degradation in the A549 tumor cell line. Compounds 1 and 2 showed hemolytic activity with half maximal inhibitory concentration (IC(50)) values around 80 microM. CONCLUSIONS: Both glycosides showed low cytotoxic activity in A549 tumor cells in comparison with sea cucumber triterpene glycosides containing a linear tetrasaccharide chain. This could be a result of the uncommon presence of two 12alpha- and 17alpha-hydroxyl groups and a Delta(7) double bond in the aglycone moiety. This aglycone functionalization may be related to their low membranolytic activity. Although glycosides 1 and 2 exert an antiproliferative effect, their mechanisms of action do not involve inhibition of NF-kappaB. Recently, it has been shown that diverse and new mechanisms of action are responsible for the antitumor and cytotoxic activities of marine compounds. Therefore, more extensive studies are needed to establish a mechanism of action and to deduce a clear structure-activity relationship of sea cucumber triterpene glycosides.