Axarli I, Labrou N E, Petrou C, Rassias N, Cordopatis P, Clonis Y D
Laboratory of Enzyme Technology, Department of Agricultural Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, GR-11855 Athens, Greece.
Eur J Med Chem. 2009 May;44(5):2009-16. doi: 10.1016/j.ejmech.2008.10.009. Epub 2008 Oct 17.
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-[Lue(13)]-bombesin, R-[Phe(13)]-bombesin and R-[Ser(3),Arg(10),Phe(13)]-bombesin, where R=C(6)H(5)SO(2)NH-) 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.
谷胱甘肽转移酶（GSTs）是一类通过催化谷胱甘肽（GSH）对多种有毒化合物和外源性物质（包括某些化疗药物）的亲电中心进行亲核攻击，从而参与细胞解毒的酶。因此，肿瘤细胞中出现的化疗耐药性与总GST表达的增加有关。GSTs除了具有GSH结合活性外，还表现出磺酰胺酶活性，催化GSH介导的磺酰胺键水解。这类反应作为潜在的肿瘤导向前药激活策略备受关注。在本研究中，我们报道了新型铃蟾肽嵌合磺酰胺衍生物的设计与合成，这些衍生物能够被人源模型同工酶GSTA1-1（hGSTA1-1）激活。这些衍生物带有一个肽基部分（铃蟾肽肽类似物：R-[Lue(13)]-铃蟾肽、R-[Phe(13)]-铃蟾肽和R-[Ser(3),Arg(10),Phe(13)]-铃蟾肽，其中R = C(6)H(5)SO(2)NH-）作为分子识别元件，用于将药物选择性地靶向肿瘤细胞。在hGSTA1-1介导的磺酰胺键裂解后释放的S-烷基谷胱甘肽，可提供对不同来源GSTs具有不同强度的抑制剂。这些前药被设想为一种使过表达GSTs的耐药肿瘤敏感化的可行手段。
