Calenduladiol

Background/aim: This study examined the potential role of natural triterpenoids lupeol, calenduladiol and heliantriol B2, and a set of 19 derivatives, as antiproliferative and antimetastatic agents against prostate cancer cells. Materials and methods: Natural triterpenoids were isolated from Chuqiraga erinaceae. Analogs were obtained by transformations of lupeol and calenduladiol. The effects of compounds on PC-3 and LNCaP cells were determined using the MTT assay. Compounds with half-maximal inhibitory concentration <70 μM were evaluated as antimetastatic agents by a wound-healing assay. Results: Lupeol-3β-sulfate, a new semisynthetic lupane, was the most active compound. In general, sulfated derivatives displayed higher activity than the lead against both cell lines. A new analog, calenduladiol-3β-monosulfate, inhibited the migration of PC-3 cells; heliantriol B2 and 3β-aminolupane inhibited the migration of LNCaP cells in a concentration-dependent manner. Conclusion: Our study provides novel agents with cytotoxic effects on prostate cancer cells, which may represent a potential new therapeutic approach for prostate cancer.

In addition to known constituents of Telekia speciosa, an acetone extract from ray florets of the plant yielded: 5,5'-dibutoxy-2,2'-bifuran (1), 5,5'-diisobutoxy-2,2'-bifuran (2), α-tocopherol (3), β-tocopherol (4), loliolide palmitate (5), a mixture of calenduladiol esters - 16β-hydroxylupeol-3-O-palmitate (7) and 16β-hydroxylupeol-3-O-myristate (8), 1-epiinuviscolide (12), inuviscolide (13), 3-epiisotelekin (16), 4α-hydroxy-9β,10β-epoxy-1β(H)-11(13)-guaien-8α,12-olide (17), 4α-hydroxy-1β(H)-9(10),11(13)-guaiadien-8α,12-olide (18), loliolide (19) and 4β,10β-dihydroxy-1α(H),5α(H)-11(13)-guaien-8α,12-olide (20). Calenduladiol esters and asperilin (14) were the major constituents of the extract. Their cytotoxic effect on human normal prostate epithelial cells (PNT-2), human prostate carcinoma cell lines, human skin fibroblasts (HSF) and human melanoma cell lines was examined in vitro. Triterpene esters showed no cytotoxicity against nearly all cell lines tested, except for Du145 prostate carcinoma cells (IC50 - 62.0 μΜ). Asperilin displayed activity against the cell lines under study, especially against three tested lines of melanomas (A375, IC50 - 17.6 μΜ, WM793, IC50 - 28.2 μΜ and Hs 294T, IC50 - 29.5 μΜ).

A set of triterpenoids with different grades of oxidation in the lupane skeleton were prepared and evaluated as cholinesterase inhibitors. Allylic oxidation with selenium oxide and Jones's oxidation were employed to obtain mono-, di- and tri-oxolupanes, starting from calenduladiol (1) and lupeol (3). All the derivatives showed a selective inhibition of butyrylcholinesterase over acetylcholinesterase (BChE vs. AChE). A kinetic study proved that compounds 2 and 9, the more potent inhibitors of the series, act as competitive inhibitors. Molecular modeling was used to understand their interaction with BChE, the role of carbonyl at C-16 and the selectivity towards this enzyme over AChE. These results indicate that oxidation at C-16 of the lupane skeleton is a key transformation in order to improve the cholinesterase inhibition of these compounds.