Abstract
An asymmetric synthesis of a series of novel 4-methyl-(3'S,4'S)-cis-khellactone derivatives 3a–o is reported for the first time. Their structures were confirmed by 1H-NMR, 13C-NMR and MS. Their cytotoxic activity was evaluated by the MTT assay against three selected human cancer cell lines: HEPG-2 (human liver carcinoma), SGC-7901 (human gastric carcinoma), LS174T (human colon carcinoma). Some compounds showed high inhibitory activity against these human cancer cell lines. Among them, compound 3a exhibited strong cytotoxicity, with IC50 values ranging from 8.51 to 29.65 μM. The results showed that 4-methyl-cis-khellactone derivatives with S,S configuration could be a potential antitumor agents.
Highlights
Khellactone coumarins, which constitute a small branch of the coumarin family, are notable because of their extensive bioactivities, including anti-HIV [1], anti-platelet aggregation [2], calcium antagonist activity [3], P-glycoprotein inhibitory ability, etc. [4,5]
Khellactone coumarins with 3'S,4'S configuration exist mainly in the plants Peucedanum praeruptorum Dunn and Peucedanum japonicum [10]
7-Hydroxy-4-methylcoumarin, a commercially available compound, was reacted with 3-chloro-3methyl-1-butyne in DMF in the presence of anhydrous potassium carbonate and potassium iodide and thermal rearrangement occurred in boiling diethylaniline to form 4-methylseselin (1) by following the procedures published previously [13,14]
Summary
Khellactone coumarins, which constitute a small branch of the coumarin family, are notable because of their extensive bioactivities, including anti-HIV [1], anti-platelet aggregation [2], calcium antagonist activity [3], P-glycoprotein inhibitory ability, etc. [4,5]. DCK [3'R,4'R-di-O-(camphanoyl-(+)-cis-khellactone] in this class, along with its derivatives, have received increasing attention due to their potent anti-HIV activity [6]. Khellactone coumarins contain two chiral carbons, C-3' and C-4', and most of the reported compounds possess 3'R,4'R configuration. 4'R-configured khellactone derivatives is crucial for anti-HIV activity [7,8,9]. More and more researchers have paisd close attention to the calcium antagonist activity and P-glycoprotein inhibitory ability of the (3'S,4'S)-cis-khellactone coumarins [11,12], whereas, other activities of (3'S,4'S)-cis-khellactone coumarins, for example, antitumor activity, have been rarely reported. All the synthesized compounds were screened against three cultured human cancer cell lines (HEPG-2, SGC-7901, LS174T). Some compounds showed potent cytotoxicity and compound 3a in particular exhibited the most significant cytotoxicity against these cancer cell lines, especially against HEPG-2 cells
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