Design, modeling, synthesis and biological activity evaluation of camptothecin-linked platinum anticancer agents

被引：48

作者：

Cincinelli, Raffaella ^{[1
]}

Musso, Loana ^{[1
]}

Dallavalle, Sabrina ^{[1
]}

Artali, Roberto ^{[2
]}

Tinelli, Stella ^{[3
]}

Colangelo, Donato ^{[4
]}

Zunino, Franco ^{[3
]}

De Cesare, Michelandrea ^{[3
]}

Beretta, Giovanni Luca ^{[3
]}

Zaffaroni, Nadia ^{[3
]}

机构：

[1] Univ Milan, Div Chem & Mol Biol, Dept Food Environm & Nutr Sci, I-20133 Milan, Italy

[2] Scientia Advice, I-20851 Lissone, MB, Italy

[3] Fdn IRCSS Ist Nazl Tumori, Mol Pharmacol Unit, Dept Expt Oncol & Mol Med, I-20133 Milan, Italy

[4] Univ Piemonte Orientale, I-28100 Novara, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 63卷

关键词：

Antitumor compounds; Docking; Camptothecin; Diaminedichloro-platinum (II); SOLID-PHASE SYNTHESIS; CELLULAR PHARMACOLOGY; TOPOISOMERASE-I; HYDROPHILIC CAMPTOTHECIN; CYTOTOXIC ACTIVITY; ANTITUMOR-ACTIVITY; CISPLATIN; DNA; COMPLEXES; CANCER;

D O I：

10.1016/j.ejmech.2013.02.022

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds. (C) 2013 Elsevier Masson SAS. All rights reserved.

引用

页码：387 / 400

页数：14

共 62 条

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