Abstract
A series of 40-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 language | English |
|---|---|
| Pages (from-to) | 1689-1699 |
| Number of pages | 11 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 36 |
| Issue number | 12 |
| Publication status | Published - 1993 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
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. / Terada, Tadafumi; Fujimoto, Katsuhiko; Nomura, Makoto; Yamashita, Jun Ichi; Wierzba, Konstanty; Yamazaki, Ryoko; Shibata, Jiro; Sugimoto, Yoshikazu; Yamada, Yuji; Kobunai, Takashi; Takeda, Setsuo; Minami, Yoshinori; Yoshida, Ken Ichirou; Yamaguchi, Hideo.
In: Journal of Medicinal Chemistry, Vol. 36, No. 12, 1993, p. 1689-1699.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Terada, Tadafumi
AU - Fujimoto, Katsuhiko
AU - Nomura, Makoto
AU - Yamashita, Jun Ichi
AU - Wierzba, Konstanty
AU - Yamazaki, Ryoko
AU - Shibata, Jiro
AU - Sugimoto, Yoshikazu
AU - Yamada, Yuji
AU - Kobunai, Takashi
AU - Takeda, Setsuo
AU - Minami, Yoshinori
AU - Yoshida, Ken Ichirou
AU - Yamaguchi, Hideo
PY - 1993
Y1 - 1993
N2 - A series of 40-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.
AB - A series of 40-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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0027208041&partnerID=8YFLogxK
M3 - Article
VL - 36
SP - 1689
EP - 1699
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 12
ER -