Antitumor Agents. 3. Synthesis and Biological Activity of 4β-Alkyl Derivatives Containing Hydroxy, Amino, and Amido Groups of 4′-O-Demethyl-4-desoxypodophyllotoxin as Antitumor Agents

Tadafumi Terada, Katsuhiko Fujimoto, Makoto Nomura, Jun ichi Yamashita, Konstanty Wierzba, Ryoko Yamazaki, Jiro Shibata, Yoshikazu Sugimoto, Yuji Yamada, Takashi Kobunai, Setsuo Takeda, Yoshinori Minami, Ken ichirou Yoshida, Hideo Yamaguchi

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Abstract

A series of 4β-alkyl (7–10), 4β-aminoalkyl (12a–y), and 4β-amidoalkyl derivatives (14a–g) of 4′-O-demethyl-4-desoxypodophyllotoxin have been synthesized, and their cytotoxicity, inhibition of DNA topoisomerase II (Topo II), and tubulin polymerization were evaluated. All derivatives of 12a–y and 14a–g did not inhibit tubulin polymerization. Many compounds exhibited cytotoxicity and inhibition of Topo II. In particular, 12o, 12s, 12t, and 12u strongly inhibited Topo II (IC50 (µM) 32.5, 60.9, 58.8, and 33.6, respectively) and were strong cytotoxicity against P388 cells (IC50 (M) 1.0, 4.1, 3.3, and 3.0 × 10−9, respectively), compared with VP-16 (IC50 (µM) 59.2, IC50 (M) 1 × 10−8, respectively). These compounds were nearly equal to or superior to VP-16 in antitumor activity in vivo (L1210, P388, and Lewis lung) and were more cytotoxic against various human cell lines in vitro than VP-16.

Original languageEnglish
Pages (from-to)1689-1699
Number of pages11
JournalJournal of Medicinal Chemistry
Volume36
Issue number12
DOIs
Publication statusPublished - 1993 Jan 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Terada, T., Fujimoto, K., Nomura, M., Yamashita, J. I., Wierzba, K., Yamazaki, R., Shibata, J., Sugimoto, Y., Yamada, Y., Kobunai, T., Takeda, S., Minami, Y., Yoshida, K. I., & Yamaguchi, H. (1993). Antitumor Agents. 3. Synthesis and Biological Activity of 4β-Alkyl Derivatives Containing Hydroxy, Amino, and Amido Groups of 4′-O-Demethyl-4-desoxypodophyllotoxin as Antitumor Agents. Journal of Medicinal Chemistry, 36(12), 1689-1699. https://doi.org/10.1021/jm00064a002