Sulphonamide-based bombesin prodrug analogues for glutathione transferase, useful in targeted cancer chemotherapy

I. Axarli, N. E. Labrou, C. Petrou, N. Rassias, P. Cordopatis, Y. D. Clonis

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Glutathione transferases (GSTs) are enzymes involved in cellular detoxification by catalysing the nucleophilic attack of glutathione (GSH) on the electrophilic centre of a number of toxic compounds and xenobiotics, including certain chemotherapeutic drugs. The encountered chemotherapeutic resistant of tumour cells, thus, has been associated with the increase of total GST expression. GSTs, in addition to GSH-conjugating activity, exhibit sulphonamidase activity, catalyzing the GSH-mediated hydrolysis of sulphonamide bonds. Such reactions are of interest as potential tumour-directed prodrug activation strategies. In the present work we report the design and synthesis of novel chimaeric sulphonamide derivatives of bombesin, able to be activated by the model human isoenzyme GSTA1-1 (hGSTA1-1). These derivatives bear a peptidyl-moiety (analogues of bombesin peptide: R-[Lue13]-bombesin, R-[Phe13]-bombesin and R-[Ser3,Arg10,Phe13]-bombesin, where R = C6H5SO2NH-) as molecular recognition element for targeting the drug selectively to tumour cells. The released S-alkyl-glutathione, after hGSTA1-1-mediated cleavage of the sulphonamide bond, provides an inhibitor of varied strength against GSTs from different sources. These prodrugs are envisaged as a plausible means to sensitize drug-resistant tumours that overexpress GSTs.

Original languageEnglish
Pages (from-to)2009-2016
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume44
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords

  • Alkylating agents
  • Antineoplastic therapy
  • Detoxification
  • Drug resistance
  • Enzyme-activated prodrug
  • Glutathione transferase

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