Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives

Zi Long Song, Mei Juan Wang, Lanlan Li, Dan Wu, Yu Han Wang, Li Ting Yan, Susan L. Morris-Natschke, Ying Qian Liu, Yong Long Zhao, Chih Ya Wang, Huanxiang Liu, Masuo Goto, Heng Liu, Gao Xiang Zhu, Kuo Hsiung Lee

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.

Original languageEnglish
Pages (from-to)109-120
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume115
DOIs
Publication statusPublished - 10 Jun 2016
Externally publishedYes

Keywords

  • Camptothecin
  • Cytotoxic activity
  • Molecular docking
  • Sulfonylamidine
  • Synthesis

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