In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence

• Published in: Journal of medicinal chemistry Vol. 62; no. 3; pp. 1541 - 1561
• Main Authors: Xu, Xin-Ya, Tsang, Siu Wai, Guan, Yi-Fu, Liu, Kang-Lun, Pan, Wen-Hui, Lam, Chu Shing, Lee, Kwan Ming, Xia, Yi-Xuan, Xie, Wen-Jian, Wong, Wing Yan, Lee, Magnolia Muk Lan, Tai, William Chi Shing, Zhang, Hong-Jie
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.02.2019; Amer Chemical Soc
• Subjects: Animals; Annonaceae - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cellular Senescence - drug effects; Chemistry, Medicinal; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclohexanols - chemical synthesis; Cyclohexanols - isolation & purification; Cyclohexanols - pharmacology; Cyclohexanones - chemical synthesis; Cyclohexanones - isolation & purification; Cyclohexanones - pharmacology; Female; Humans; Life Sciences & Biomedicine; Male; Mice, Inbred BALB C; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Signal Transduction - drug effects; Spiro Compounds - chemical synthesis; Spiro Compounds - isolation & purification; Spiro Compounds - pharmacology; Structure-Activity Relationship; Xenograft Model Antitumor Assays; APOPTOSIS; P16; ROLES; NATURAL-PRODUCTS; MECHANISMS; AGENTS; INHIBITORS; CANCER; P21; P53
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01742

Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1–19), including 11 novel ones (5 and 10–19) from another Miliusa plant (M. balansae), and synthesized additional derivatives to elucidate the structure–activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5–40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1–3 (GI50 0.03–4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.