Synthesis And Antitumor Activity Of 6-methyl-(3’S,4’S)-ciskhellactone Derivatives

Objective:Khellactone coumarins are the main kind of 7,8-pyanocoumarins, and are mianly distributed in Umbelliferae plant group, such as Peucedanum praeruptorum ect. Pharmacological research found that khellactone coumarins have a lot of activities, such as anti-HIV, antitumor, dilation of blood vessels. Previously, our research group has prepared a series of khellactone coumarins derivatives by total method, and their antitumor activity was measured. On the basis of this, in this paper, we synthesized a series of 6-methyl khellactone derivatives by introducing methyl in position C-6 and different acyl in postion C-3’ and C-4’ of khellactone coumarins skeleton. Also, the compounds’ antitumor activities were screened. Methods:The synthesis was started with 2,4-Dihydroxy toluene, followed by reduction reaction, Vilsmeier-Haack reaction, Wittig reaction to obtained 6-methyl 7-hydroxycoumarin. Then, 6-methylseselin was got by means of nucleophilic substitution reaction and Claisen rearrangement reaction. Finally, the target compounds were afforded through Sharpless asymmetrical dihydroxylation reaction and esterification reaction. Their antitumor activities against SGC-7901, HEPG-2, and EC were observed by MTT assay. Results:In this paper, we synthesized twenty one 6-methyl-(3’S,4’S)-cis-khellactone derivatives. The chemical structures were characterized by 1H-NMR, 13C-NMR, ESI-MS techniques. The in vitro antitumor assay indicated that compounds 6c, 6n and 6t were the most potent molecules with IC50 values ranging from 16.31 to 27.82, 20.80 to 23.10, 22.56 to 29.97 μM, respectively. Preliminary structure activity relationship indicated that the antitumor activity rely on the size and spatial geometry of aromatic group at 3’- and 4’- position. However, improvement of cell growth inhibition is not observed when the 3’- and 4’-position are substituted with aliphatic group. Also, the substituted group with α,β-unsaturated ketone structure benefits the potency. Flow cytometry analysis showed that compound 6c inhibited the growth of SGC-7901 by inducing apoptosis. Conclusion:6-methyl-(3’S,4’S)-cis-khellactone derivatives have a cetain degree of antitumor activity. Preliminary structure activity relationship provided the basis for further design, synthesis and optimization of khellactone coumarins.