Synthesis and in vitro cancer cell growth inhibition evaluation of 11-amino-modified 5-Me-indolo[2,3-b]quinolines and their COMPARE analyses

Masashi Okada, Zhen Wu Mei, Md Imran Hossain, Li Wang, Taihei Tominaga, Takeshi Takebayashi, Masaharu Murakami, Mizuki Yasuda, Tsukasa Shigehiro, Tomonari Kasai, Akifumi Mizutani, Hiroshi Murakami, Ibrahim El Tantawy El Sayed, Shingo Dan, Takao Yamori, Masaharu Seno, Tsutomu Inokuchi

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Abstract

A plant-derived neocryptolepine core, the 5-Me-indolo[2,3-b]quinoline skeleton, was emblazoned with substituents at C11 and C2 and then tested against various cancer cell lines to find potent anticancer agents. In the in vitro antiproliferative activity assay against the breast cancer MDA-MB-453 cell line, the attachment of alkylamino substituents at C11 of the 5-Me-indolo[2,3-b]quinoline induced improved activities. Specifically, 11-(3-aminopropylamino) and 11-(4-aminobutylamino) derivatives indicated the highest activity and selectivity against MDA-MB-453 (IC50 = 0.3-0.5 μM) and also exhibited a higher cytotoxicity against the colon adenocarcinoma (WiDr) and ovarian cancer (SKOv3) cell lines. A synergistic effect by attachment of substituents at C2 was favorably observed with an electron-donating group, such as CH3O, and unfavorably observed with an electron-withdrawing one, such as F and CF3. Further modification of the terminal free amino group of the lariat attachment at C11 into the corresponding acylamides and 2,3-dihydrobenzo[e][1,3]thiazin-4-ones was not effective for the antiproliferative activity. The computer-assisted database analysis, COMPARE, suggested that 14e and 13b have a mode of action similar to actinomycin D and 13c has a mode of actions similar to vindesine sulfate or aclarubicin hydrochloride. However, the new compounds may have other unique mode of actions since the correlation coefficients (r) were in relatively low levels.

Original languageEnglish
Pages (from-to)879-892
Number of pages14
JournalMedicinal Chemistry Research
Volume25
Issue number5
DOIs
Publication statusPublished - May 1 2016

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Keywords

  • 5Me-indolo[2,3-b]quinoline
  • Antiproliferative agent
  • C11-alkylamino-substituted
  • COMPARE study
  • JFCR39 panel
  • MDA-MB-453

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Okada, M., Mei, Z. W., Imran Hossain, M., Wang, L., Tominaga, T., Takebayashi, T., Murakami, M., Yasuda, M., Shigehiro, T., Kasai, T., Mizutani, A., Murakami, H., El Sayed, I. E. T., Dan, S., Yamori, T., Seno, M., & Inokuchi, T. (2016). Synthesis and in vitro cancer cell growth inhibition evaluation of 11-amino-modified 5-Me-indolo[2,3-b]quinolines and their COMPARE analyses. Medicinal Chemistry Research, 25(5), 879-892. https://doi.org/10.1007/s00044-016-1508-z