2. Academic Validation
  3. Synthesis of novel guttiferone E and xanthochymol derivatives with cytotoxicities by inducing cell apoptosis and arresting the cell cycle phase

Synthesis of novel guttiferone E and xanthochymol derivatives with cytotoxicities by inducing cell apoptosis and arresting the cell cycle phase

  • Eur J Med Chem. 2019 Jan 15:162:765-780. doi: 10.1016/j.ejmech.2018.11.046.
Xin Lin 1,  Dongsong Tian 2,  Yanhui Fu 3,  Yanan Li 2,  Liejun Huang 2,  Wei Gu 2,  Jialei Song 2,  Yanmei Li 2,  Yaacov Ben-David 2,  Min Wen 4,  Chunmao Yuan 5,  Xiaojiang Hao 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, 550014, PR China; College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550004, PR China.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, 550014, PR China.
  • 3 Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal University, Haikou, 571158, Hainan, PR China.
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, 550014, PR China; College of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550004, PR China. Electronic address: wenmin1112@sina.com.
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, 550014, PR China. Electronic address: yuanchunmao01@126.com.
  • 6 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, PR China; Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, 550014, PR China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, PR China. Electronic address: haoxj@mail.kib.ac.cn.
PMID: 30500683 DOI: 10.1016/j.ejmech.2018.11.046
Abstract

The mixture of GX (guttiferone E and xanthochymol), an inseparable polycyclic polyprenylated acylphloroglucinol (PPAP), showed moderate cytotoxic activities. The chemical transformation of GX yielded three different types of PPAPs (1, 2, and 3/4). A series of analogs were prepared, and the structures of the 40 newly synthesized compounds were elucidated by 1D and 2D NMR and HR-ESI-MS. The derivatives were screened in vitro for antiproliferative activity against five human Cancer cell lines: human leukemic cell lines (HEL and K562), cervical Cancer cell line (Hela), human breast adenocarcinoma cell line (MCF-7), and human non-small cell lung Cancer cell line (A549), using the MTT assay, and most of the derivatives showed good cytotoxic activities. Noticeably, compound 2, a novel tautomer with a hemiketal, exhibited selective cytotoxic activities against HEL (IC50 = 4.79 ± 0.23 μM) and K562 (IC50 = 7.69 ± 0.34 μM) leukemia cells. The mechanism studies indicated that compound 2 induced Apoptosis and arrested the cell cycle at the G0/G1 phase in the HEL cell line. Furthermore, compound 2 activated the intrinsic pathway by reducing the expression of anti-apoptotic protein Bcl-2 and cell cycle-specific cyclin D1 and by enhancing the pro-apoptotic protein Bax. Moreover, the Caspase-3 and PPRP1 levels were also upregulated. Our present results suggest that compound 2 is a potential candidate for developing novel anti-leukemia agents in the future.

Keywords

Cell apoptosis; Cell cycle arrest; Chemical transformation; Cytotoxicity; Polycyclic polyprenylated acylphloroglucinol.

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