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

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.

The work presents the synthesis of novel chimaeric sulphonamide-bombesin prodrug analogues (the structure of the prodrug sulphonamide [Ser3,Arg10,Phe13]-bombesin is shown) susceptible to activation by the human enzyme glutathione S-transferase (isoenzyme hGSTA1-1; the interaction of the sulphanilamide lead-ligand with the isoernzyme is shown). Followed GST-mediated cleavage of the sulfonamide bond, the prodrug releases a potent GST inhibitor. The decrease of GST activity is associated with a decrease of tumour cells resistance to antineoplastic agents and a more effective cancer chemotherapy.Figure optionsDownload as PowerPoint slide