2. Academic Validation
  3. Design, synthesis and potent cytotoxic activity of novel 7-(N-[(substituted-sulfonyl)piperazinyl]-methyl)-camptothecin derivatives

Design, synthesis and potent cytotoxic activity of novel 7-(N-[(substituted-sulfonyl)piperazinyl]-methyl)-camptothecin derivatives

  • Bioorg Med Chem Lett. 2017 Apr 15;27(8):1750-1753. doi: 10.1016/j.bmcl.2017.02.066.
Gao-Xiang Zhu 1,  Pi-Le Cheng 1,  Masuo Goto 2,  Na Zhang 1,  Susan L Morris-Natschke 2,  Kan-Yen Hsieh 2,  Guan-Zhou Yang 1,  Qian-Ru Yang 1,  Ying-Qian Liu 3,  Hai-Le Chen 1,  Xiao-Shuai Zhang 1,  Kuo-Hsiung Lee 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
  • 2 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
  • 3 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: yqliu@lzu.edu.cn.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@email.unc.edu.
PMID: 28285912 DOI: 10.1016/j.bmcl.2017.02.066
Abstract

In an effort to discover potent camptothecin-derived antitumor agents, novel camptothecin analogues with sulfonylpiperazinyl motifs at position-7 were designed and synthesized. They were evaluated for in vitro cytotoxicity with the sulforhodamine-B (SRB) method in five types of human tumor cell lines, A-549, MDA-MB-231, KB, KB-VIN and MCF-7. With IC50 values in the low μM to nM level, most of the new analogues showed greater cytotoxicity activity than the reference compounds irinotecan and topotecan. Furthermore, compounds 12l (IC50, 1.2nM) and 12k (IC50, 20.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating Cancer, including MDR phenotype. Our study suggested that integration of sulfonylpiperazinyl motifs into position-7 of camptothecin is an effective strategy for discovering new potent cytotoxic camptothecin derivatives.

Keywords

Camptothecin; Cytotoxic activity; Sulfonylpiperazine; Synthesis.

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