Abstract
The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic activity, two of them being in clinical use as antitumor drugs. We have synthesized a new series of camptothecins substituted in position 7 with an alkyl or alkenyl chain bearing cyano and/or carbethoxy groups. These compounds showed potent cytotoxic activity in vitro against the human non-small-cell lung carcinoma H460 cell line, most of them exhibiting IC50 values in the 0.05-1 μM range, more active than topotecan used as a reference compound. In particular 7-cyano-20S-camptothecin (5a) showed high in vitro cytotoxicity against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplatin-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evaluation of the antitumor activity, 5a appeared significantly more effective than topotecan in the H460 tumor model and comparable with topotecan in a small-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinical development.
| Original language | English |
|---|---|
| Pages (from-to) | 3963-3969 |
| Number of pages | 7 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 43 |
| Issue number | 21 |
| DOIs | |
| Publication status | Published - Oct 19 2000 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
Novel 7-substituted camptothecins with potent antitumor activity. / Dallavalle, S.; Delsoldato, T.; Ferrari, A.; Merlini, L.; Penco, S.; Carenini, N.; Perego, P.; De Cesare, M.; Pratesi, G.; Zunino, F.
In: Journal of Medicinal Chemistry, Vol. 43, No. 21, 19.10.2000, p. 3963-3969.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel 7-substituted camptothecins with potent antitumor activity
AU - Dallavalle, S.
AU - Delsoldato, T.
AU - Ferrari, A.
AU - Merlini, L.
AU - Penco, S.
AU - Carenini, N.
AU - Perego, P.
AU - De Cesare, M.
AU - Pratesi, G.
AU - Zunino, F.
PY - 2000/10/19
Y1 - 2000/10/19
N2 - The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic activity, two of them being in clinical use as antitumor drugs. We have synthesized a new series of camptothecins substituted in position 7 with an alkyl or alkenyl chain bearing cyano and/or carbethoxy groups. These compounds showed potent cytotoxic activity in vitro against the human non-small-cell lung carcinoma H460 cell line, most of them exhibiting IC50 values in the 0.05-1 μM range, more active than topotecan used as a reference compound. In particular 7-cyano-20S-camptothecin (5a) showed high in vitro cytotoxicity against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplatin-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evaluation of the antitumor activity, 5a appeared significantly more effective than topotecan in the H460 tumor model and comparable with topotecan in a small-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinical development.
AB - The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic activity, two of them being in clinical use as antitumor drugs. We have synthesized a new series of camptothecins substituted in position 7 with an alkyl or alkenyl chain bearing cyano and/or carbethoxy groups. These compounds showed potent cytotoxic activity in vitro against the human non-small-cell lung carcinoma H460 cell line, most of them exhibiting IC50 values in the 0.05-1 μM range, more active than topotecan used as a reference compound. In particular 7-cyano-20S-camptothecin (5a) showed high in vitro cytotoxicity against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplatin-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evaluation of the antitumor activity, 5a appeared significantly more effective than topotecan in the H460 tumor model and comparable with topotecan in a small-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinical development.
UR - http://www.scopus.com/inward/record.url?scp=0034687256&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034687256&partnerID=8YFLogxK
U2 - 10.1021/jm000944z
DO - 10.1021/jm000944z
M3 - Article
C2 - 11052801
AN - SCOPUS:0034687256
VL - 43
SP - 3963
EP - 3969
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 21
ER -