2. Academic Validation
  3. Synthesis and biological evaluation of D-ring fused 1,2,3-thiadiazole dehydroepiandrosterone derivatives as antitumor agents

Synthesis and biological evaluation of D-ring fused 1,2,3-thiadiazole dehydroepiandrosterone derivatives as antitumor agents

  • Eur J Med Chem. 2016 Mar 23:111:126-37. doi: 10.1016/j.ejmech.2016.01.058.
Hai-Wei Cui 1,  Shihong Peng 2,  Xiang-Zhong Gu 3,  Huang Chen 2,  Yuan He 2,  Wei Gao 1,  Fang Lv 2,  Jin-Hua Wang 2,  Yan Wang 1,  Jia Xie 2,  Ming-Yao Liu 2,  Zhengfang Yi 4,  Wen-Wei Qiu 5
Affiliations

Affiliations

  • 1 Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 3 Department of Research and Development, Jiangsu Jiaerke Pharmaceuticals Group Co., Ltd., Zhenglu Town, Changzhou 213111, China.
  • 4 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: zfyi@bio.ecnu.edu.cn.
  • 5 Department of Chemistry, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. Electronic address: wwqiu@chem.ecnu.edu.cn.
PMID: 26866967 DOI: 10.1016/j.ejmech.2016.01.058
Abstract

A series of D-ring fused 1,2,3-thiadiazole DHEA derivatives were synthesized and investigated for their activity against the growth of various tumor cell lines using the sulforhodamine B (SRB) assay. It is amazing that for these compounds, T47D cell line was much more sensitive than Other tumor cell lines. The most potent saturated N-heterocyclic derivatives showed similar antitumor effect with the positive control compound ADM (adriamycin) on T47D cells, that was 44-60 folds more potent than the lead compound DHEA. Most compounds with potent antitumor activity displayed low toxicity on normal human fibroblasts (HAF). Especially compound 25 (CH33) showed an IC50 of 0.058 μM on T47D cells and its selectivity index (SI) between HAF and T47D was 364, which was 214 folds better than ADM (SI = 1.7). The Apoptosis, colony formation and transwell migration assays of 25 were performed on T47D cell line. The primary mechanism study showed that 25 caused a dose-dependent induction of Apoptosis, and induced phosphorylation of EphA2 and EphB3 in T47D cells. The in vivo antitumor effect of 25 was also observed in T47D tumor-bearing mice without obvious toxicity.

Keywords

1,2,3-Thiadiazole; Antitumor; Apoptosis; Dehydroepiandrosterone; Migration.

Figures