Camptothecin and thiocamptothecin: The role of sulfur in shifting the hydrolysis equilibrium towards the closed lactone form

Marco Pistolozzi, Greta Varchi, Alessandra Degli Esposti, Andrea Guerrini, Giovanna Sotgiu, Marco Ballestri, Claudia Ferroni, Alessandro Venturini, Carlo Bertucci

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Adverse effects have limited the clinical potential of 20-(S)-camptothecin (CPT) and led to a growing interest in the development of CPT analogues that exhibit less severe drawbacks, while maintaining their therapeutic activity. Recently, a thiopyridone isostere of CPT, 20-(S)-thiocamptothecin (TCPT), was developed that resulted more potent than the parent compound in H460, HT29 and IGROV-1 cell lines. The improved activity of TCPT over CPT might be due to the greater stability of the lactone ring. Here, reversible hydrolysis to the ring-open carboxylate forms of CPT and TCPT was studied by HPLC, both in the presence and absence of human serum albumin (HSA). The amount of TCPT that exists in the lactone form at equilibrium in buffer solution (24h) was found to be significantly higher than CPT, and the same trend was observed in the presence of HSA. Specifically, HSA caused a shift in the hydrolysis equilibrium of TCPT towards the carboxylate form, but the proportion of lactone form remained higher than that observed for CPT under the same conditions, and also in the presence of a higher excess of the protein. The role of the sulfur atom in the stability of the open and closed lactone derivatives was investigated by theoretical calculations using stabilization energies and comparison between experimental and calculated absorption spectra. Our results suggest that, in aqueous solution, more ionic species (anionic and enolic forms) are present for TCPT. This study provides further insights into the effects of oxygen/sulfur replacement in the CPT pyridone ring.

Original languageEnglish (US)
Pages (from-to)1706-1714
Number of pages9
JournalChemMedChem
Volume6
Issue number9
DOIs
StatePublished - Sep 5 2011

Keywords

  • Absorption spectroscopy
  • Camptothecins
  • Computational chemistry
  • Density functional theory
  • Liquid chromatography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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