Novel 7-substituted camptothecins with potent antitumor activity

S. Dallavalle, T. Delsoldato, A. Ferrari, L. Merlini, S. Penco, N. Carenini, P. Perego, M. De Cesare, G. Pratesi, F. Zunino

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)3963-3969
Number of pages7
JournalJournal of Medicinal Chemistry
Volume43
Issue number21
DOIs
Publication statusPublished - Oct 19 2000

Fingerprint

Topotecan
Camptothecin
Cells
Antineoplastic Agents
Bearings (structural)
Lead compounds
Carcinoma
Type I DNA Topoisomerase
Small Cell Lung Carcinoma
Cytotoxicity
Alkaloids
Non-Small Cell Lung Carcinoma
Cisplatin
Inhibitory Concentration 50
Tumors
Colon
Pharmacology
Derivatives
Cell Line
Neoplasms

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Dallavalle, S., Delsoldato, T., Ferrari, A., Merlini, L., Penco, S., Carenini, N., ... Zunino, F. (2000). Novel 7-substituted camptothecins with potent antitumor activity. Journal of Medicinal Chemistry, 43(21), 3963-3969. https://doi.org/10.1021/jm000944z

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 journalArticle

Dallavalle, S, Delsoldato, T, Ferrari, A, Merlini, L, Penco, S, Carenini, N, Perego, P, De Cesare, M, Pratesi, G & Zunino, F 2000, 'Novel 7-substituted camptothecins with potent antitumor activity', Journal of Medicinal Chemistry, vol. 43, no. 21, pp. 3963-3969. https://doi.org/10.1021/jm000944z
Dallavalle S, Delsoldato T, Ferrari A, Merlini L, Penco S, Carenini N et al. Novel 7-substituted camptothecins with potent antitumor activity. Journal of Medicinal Chemistry. 2000 Oct 19;43(21):3963-3969. https://doi.org/10.1021/jm000944z
Dallavalle, S. ; Delsoldato, T. ; Ferrari, A. ; Merlini, L. ; Penco, S. ; Carenini, N. ; Perego, P. ; De Cesare, M. ; Pratesi, G. ; Zunino, F. / Novel 7-substituted camptothecins with potent antitumor activity. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 21. pp. 3963-3969.
@article{de8cec49e7944d09a7170a40daaee878,
title = "Novel 7-substituted camptothecins with potent antitumor activity",
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.",
author = "S. Dallavalle and T. Delsoldato and A. Ferrari and L. Merlini and S. Penco and N. Carenini and P. Perego and {De Cesare}, M. and G. Pratesi and F. Zunino",
year = "2000",
month = "10",
day = "19",
doi = "10.1021/jm000944z",
language = "English",
volume = "43",
pages = "3963--3969",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

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 -