NMR-Based Chemical Profiling, Isolation and Evaluation of the Cytotoxic Potential of the Diterpenoid Siderol from Cultivated Sideritis euboea Heldr.

Abstract

Diterpenes are characteristic compounds from the genus Sideritis L., possessing an array of biological activities. Siderol is the main constituent of the ent-kaurene diterpenes in Sideritis species. In order to isolate the specific compound and evaluate for the first time its cytotoxic activity, we explored the dichloromethane extract of cultivated Sideritis euboea Heldr. To track the specific natural bioactive agent, we applied NMR spectroscopy to the crude plant extract, since NMR can serve as a powerful and rapid tool both to navigate the targeted isolation process of bioactive constituents, and to also reveal the identity of bioactive components. Along these lines, from the rapid 1D 1H NMR spectrum of the total crude plant extract, we were able to determine the characteristic proton NMR signals of siderol. Furthermore, with the same NMR spectrum, we were able to categorize several secondary metabolites into chemical groups as a control of the isolation process. Therefore, this non-polar extract was explored, for the first time, revealing eleven compounds—one fatty acid ester; 2-(p-hydroxyphenyl)ethylstearate (1), three phytosterols; β-sitosterol (2), stigmasterol (3), and campesterol (4); one triterpenoid; ursolic acid (5), four diterpenoids; siderol (6), eubol (7), eubotriol (8), 7-epicandicandiol (9) and two flavonoids; xanthomicrol (10) and penduletin (11). The main isolated constituent was siderol. The antiproliferative potential of siderol was evaluated, using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay, on three human cancer cell lines DLD1, HeLa, and A549, where the IC50 values were estimated at 26.4 ± 3.7, 44.7 ± 7.2, and 46.0 ± 4.9 μΜ, respectively. The most potent activity was recorded in the human colon cancer cell line DLD1, where siderol exhibited the lowest IC50. Our study unveiled the beneficial potential of siderol as a remarkable cytotoxic agent and the significant contribution of NMR spectroscopy towards the isolation and identification of this potent anticancer agent.

Bio‐Guided Investigation of Sideritis cypria Methanol Extract Driven by in Vitro Antioxidant and Cytotoxic Assays

“…Furthermore, compounds 28 and 29 correspond to fatty acid derivatives and their bioactivity has not been explored up to date. It is noteworthy that compound 29 has been recently isolated from S. euboea [49] and it was not identified in other Sideritis species, previously. Gathering all the above data, the present investigation reveals the presence of compounds 2 – 4 , 7 – 10 , 13 , 14 , 22 , 24 – 29 for the first time in S. cypria .…”

“…It is interesting that compound 7 was isolated from several Sideritis species, but not from S. cypria [45] . Moreover, compounds 8 and 9 are two very common phytosterols in genus Sideritis , [46–49] exerting numerous pharmacological activities [50–52] . It is intriguing to point out that compounds 5 – 9 were isolated from a polar extract, though they are generally characterized as mainly non‐polar secondary specialized products.…”

Anti-Ageing Potential of S. euboea Heldr. Phenolics

“…Compounds 1 – 3 were isolated from the non-polar fractions of the plant residue. This study represents the first report of triolein in genus Sideritis , whereas compounds 2 and 3 were extensively found in this genus and might also be characteristic compounds for the specific species [ 4 , 9 , 41 ]. Furthermore, the three isolated iridoids (compounds 4 – 6 ) were previously reported on genus Sideritis [ 8 , 42 , 43 , 44 ].…”

“…Traditionally, its infusion (known as mountain tea) is widely consumed against mild gastrointestinal discomfort and common flu [ 5 , 6 , 7 , 8 ]. Previous studies reported the rich chemical profile of its extracts, including various metabolites with significant pharmacological effects [ 4 , 5 , 6 , 7 , 8 , 9 ]. The constantly increasing demand for mountain tea results in serious concerns about the survival of the wild Sideritis populations due to their overharvesting.…”

Anti-Colorectal Cancer Effects of Medicinal Plants: Euphorbia helioscopia, Ferula elaeochytris, and Sideritis albiflora

“…Previously, the infusion of Sideritis syriaca was reported to inhibit HT-29 cell growth with value of ~ 60% at 1.00 µg/µL concentration after 48 h by Kogiannou et al (2013). The IC50 value of siderol, a well-known major constituent of the genus Sideritis, was calculated as 26.4±3.7 µM in DLD-1 cell line (Tomou et al, 2020). The hexane extract of Ferula hermonis root (IC50: 25 µg/mL) was found to have moderate sensitivity on the LoVo cell line (Abutaha et al, 2019).…”