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

Raffaella Cincinelli, Loana Musso, Sabrina Dallavalle, Roberto Artali, Stella Tinelli, Donato Colangelo, Franco Zunino, Michelandrea De Cesare, Giovanni Luca Beretta, Nadia Zaffaroni

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)387-400
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume63
DOIs
Publication statusPublished - 2013

Keywords

  • Antitumor compounds
  • Camptothecin
  • Diaminedichloro-platinum (II)
  • Docking

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Fingerprint

Dive into the research topics of 'Design, modeling, synthesis and biological activity evaluation of camptothecin-linked platinum anticancer agents'. Together they form a unique fingerprint.

Cite this