In vitro cytotoxic potential of novel semi-synthesised clusianone and cardamonin analogues

Secondary metabolites derived from natural products are extremely diverse with wide-ranging biomedical implications. In an effort to establish new candidates with improved cytotoxic activity, two naturally occurring compounds, namely clusianone and cardamonin, have been investigated due to their potent cytotoxic activities [1]. Clusianone extracted from the leaves of Garcinia parvifolia and commercially available cardamonin were used as starting materials for the semi-synthesis of 7 and 15 analogues respectively. Synthesised clusianone analogues mainly involved alterations to the hydroxyl group via acylation and alkylation reactions while cardamonin analogues involved modifications of carbonyl group via reduction and condensation reactions. Most compounds were characterised via melting point measurements, IR and mass spectrometry while further analysis has been performed via ¹H NMR. All of the synthesised compounds were subjected to in vitro cytotoxic evaluation against squamous nasopharynx cells (HK1) and lung adenocarcinoma cells (A549) in the concentration range of 6.25 – 100 µM. Results revealed the importance of the hydroxyl group for clusianone's cytotoxicity, whereby its modification resulted in a loss of activity. On the contrary, modification of the carbonyl group of cardamonin enhanced cytotoxicity. Metal complexes of both natural products exhibited improved bioactivity as evident from copper complexes. The overall data obtained revealed significant cytotoxicity against both cell lines, with IC₅₀ below 10 µM after 72h treatment for some of the analogues tested. The above results warrant further research into elucidating the mode of action of these promising lead compounds as well as establishing a concise SAR study.

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[1] Simpkins NS, Holtrup F, Rodeschini V, Taylor JD, Wolf R. Comparison of the cytotoxic effects of enantiopure PPAPs, including nemorosone and clusianone. Bioorg Med Chem Lett 2012; 22: 6144 – 6147