2. Academic Validation
  3. Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents

Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents

  • Bioorg Med Chem. 2015 May 1;23(9):1950-62. doi: 10.1016/j.bmc.2015.03.031.
Lei Wang 1,  Shao Xie 2,  Longjun Ma 1,  Yi Chen 3,  Wei Lu 4
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
  • 2 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 3 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: ychen@simm.ac.cn.
  • 4 School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
PMID: 25835359 DOI: 10.1016/j.bmc.2015.03.031
Abstract

Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon Cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential Anticancer clinical trial candidates is definitely warranted.

Keywords

Anticancer drug; Homocamptothecin; Lactone stability; Water solubility.

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