SAR study and antitumor potential of plant natural product miliusanes and their derivatives

In our previous research, bioassay-directed fractionation of Miliusa sinensis Finet & Gagnep. (Annonaceae) led to the discovery of miliusane anticancer lead molecules [1]. As a continuous study, we have investigated the chemical constituents of another plant species (M. balansae) in the same genus. Separation of the dichloromethane extract of this plant led to the isolation of 8 known miliusanes including miliusate (1) and miliusol (2), the potent antitumor compounds discovered in our previous study. In this study, we investigated the in vivo antitumor activity of the miliusane compounds using the hollow fibre as well as the xenograft mouse models. The animal studies demonstrated the antitumor potency of miliusol is comparable with that of the clinically used drug paclitaxel, but with lower toxicity. In order to determine the structure-activity relationship (SAR) of miliusanes, we further synthesized 15 miliusane derivatives (3-17). From the SAR study, we found that although the α, β-unsaturated carbonyl structure played an important role in cytotoxicity for some miliusanes, this functional group is not essential for the bioactivity of miliusanes. Indeed, the two Michael addition products 13 and 14, which contained no α, β-unsaturated carbonyl, showed equivalent cancer cell killing activities (IC₅₀ against HCT116: 1.88 and 1.83µM, respectively) as those of miliusate and miliusol. An α, β-unsaturated carbonyl structure has been known to contribute to the biological activities of many compounds. However, the same functional group may also cause severe side effects because of its reactivity with many protein receptors. By eliminating the functional group while retain the bioactivity, compounds such as 13 and 14 may have less toxicity in comparison with miliusol and miliusate. This SAR study will provide us valuable information for rational design to synthesize miliusane analogs as druggable candidates for anticancer treatment.

Acknowledgements: The work described in this paper was supported by the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKBU 12103014) and HKBU Interdisciplinary Research Matching Scheme (RC-IRMS/12 – 13/03).

Keywords: Miliusane, Miliusa balansae, isolation and identification, structure modification, antitumor activity, in vivo activity.

References:

[1] Zhang HJ, Ma CY, Hung VN et al. Miliusanes, A class of cytotoxic agent from Miliusa sinensis. J Med Chem 2006; 49: 693 – 708