Camptothecin and Thiocamptothecin: the Role of Sulfur in Shifting the Hydrolysis Equilibrium towards the Closed Lactone Form (Articolo in rivista)

Type
Label
  • Camptothecin and Thiocamptothecin: the Role of Sulfur in Shifting the Hydrolysis Equilibrium towards the Closed Lactone Form (Articolo in rivista) (literal)
Anno
  • 2011-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1002/cmdc.201100206 (literal)
Alternative label
  • Pistolozzi, M (1); Varchi, G (2); Degli Esposti, A (2); Guerrini, A (2); Sotgiu, G (2); Ballestri, (2); Ferroni, C (2); Venturini, A (2); Bertucci, C (1) (2011)
    Camptothecin and Thiocamptothecin: the Role of Sulfur in Shifting the Hydrolysis Equilibrium towards the Closed Lactone Form
    in ChemMedChem (Internet)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Pistolozzi, M (1); Varchi, G (2); Degli Esposti, A (2); Guerrini, A (2); Sotgiu, G (2); Ballestri, (2); Ferroni, C (2); Venturini, A (2); Bertucci, C (1) (literal)
Pagina inizio
  • 1706 (literal)
Pagina fine
  • 1714 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url
  • http://dx.doi.org/10.1002/cmdc.201100206 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 6 (literal)
Rivista
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • (1): Univ Bologna, Dept Pharmaceut Sci, I-40126 Bologna, Italy (2): CNR, Inst Organ Synth & Photoreact, I-40129 Bologna, Italy (literal)
Titolo
  • Camptothecin and Thiocamptothecin: the Role of Sulfur in Shifting the Hydrolysis Equilibrium towards the Closed Lactone Form (literal)
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 (24 h) 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. (literal)
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