Short Lecture "Search for diversified miliusane compounds from Miliusa plants for anticancer drug discovery"

Plants have been a constant source to provide bioactive compounds. During our exploration of the plant biodiversity of the regions in Southeast Asia, miliusanes have been discovered as a cluster of novel anticancer compounds from the Miliusa genus. Miliusanes are unique natural products with a γ-lactone spiro-ring system skeleton containing 18 carbons formed from a geranyl and homogentisic acid ([Fig. 1]). We have isolated dozens of new miliusanes from Miliusa medicinal plants, and many of them have demonstrated with cancer cell killing activities against multiple cancer cell lines. The structures of the natural miliusanes are diversified, but their bioactivities depend on several key functional groups, which provided a viable strategy for functional group based-structure modification to obtain miliusane derivatives with enhance activities. We have then synthesised various miliusane analogues, and analysed their structural-activity relationship (SAR). Several miliusanes were selected for further evaluation in the tumour- bearing mouse models, and they have been found to potently inhibit tumour growth against several types of cancer cells with low toxicity when compared with the clinically used drugs paclitaxel (PTX) and fluorouracil (5-FU). Our further biological studies determined that the anti-proliferative activities of miliusanes on cancer cells were positively correlated with their induction of senescence, rather than apoptosis. This experimental evidence clearly indicated miliusanes as promising lead molecules that have high potential for development as novel therapeutic drugs against cancerous diseases.

Fig. 1 a) Chemical skeleton and activity associated key functional groups of miliusanes. b) Naturally occurred bioactive miliusanes and their synthetic derivatives (R=H, Ac, Ph, etc.; R₁=H, CH₃, Ph, etc.; R₁=H, Ac, Ph, etc.; X=O, NH, etc.).

Acknowledgement: This work is supported by the HKBU Initiation Grant for Faculty Niche Research Areas (IG-FNRA) 2021/22 (RC-IGFNRA/21-22/SCM/01).

 

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Conflict of Interest

The authors declare no conflict of interest.

Publikationsverlauf

Artikel online veröffentlicht:
16. November 2023