2. Academic Validation
  3. Hydrogen sulfide donating ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane derivatives: Design, synthesis and antiproliferative properties

Hydrogen sulfide donating ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane derivatives: Design, synthesis and antiproliferative properties

  • Eur J Med Chem. 2019 Sep 15:178:446-457. doi: 10.1016/j.ejmech.2019.06.016.
Haonan Li 1,  Xiang Gao 1,  Xiaofang Huang 1,  Xianhua Wang 2,  Shengtao Xu 3,  Takahiro Uchita 4,  Ming Gao 4,  Jinyi Xu 3,  Huiming Hua 1,  Dahong Li 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China.
  • 2 School of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, PR China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 4 School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, Nishinomiya, 663-8179, Japan.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China. Electronic address: lidahong0203@163.com.
PMID: 31202992 DOI: 10.1016/j.ejmech.2019.06.016
Abstract

Motivated by our interest in hydrogen sulfide bio-chemistry and ent-kaurane diterpenoid chemistry, 14 hydrogen sulfide donating derivatives (9, 11a-c, 12a-c, 13, 14, 16a-c and 17a-b) of ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane were designed and synthesized. Four human Cancer cell lines (K562, Bel-7402, SGC-7901 and A549) and two normal cell lines (L-02 and PBMC) were selected for antiproliferative assay. Most derivatives showed more potent activities than the lead ent-kaurane oridonin. Among them, compound 12b exhibited the most potent antiproliferative activities, with IC50 values of 1.01, 0.88, 4.36 and 5.21 μM against above human Cancer cell lines, respectively. Further apoptosis-related mechanism study indicated that 12b could arrest Bel-7402 cell cycle at G1 phase and induce Apoptosis through mitochondria related pathway. Through Western blot assay, 12b was shown to influence the intrinsic pathway by increasing the expression of Bax, cleaved Caspase-3, cytochrome c and cleaved PARP, meanwhile suppressing procaspase-3, Bcl-2, Bcl-xL and PARP.

Keywords

Antiproliferative activity; Apoptosis; Diterpenoid; Hydrogen sulfide.

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