School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Dublin 2, Ireland.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Trinity College Dublin, Dublin 2, Ireland.
Eur J Med Chem. 2017 Apr 21;130:261-285. doi: 10.1016/j.ejmech.2017.02.049. Epub 2017 Feb 24.
Glucuronidation by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) is a cause of intrinsic drug resistance in cancer cells. Glucuronidation of combretastatin A-4 (CA-4) was previously identified as a mechanism of resistance in hepatocellular cancer cells. Herein, we propose chemical manipulation of β-lactam bridged analogues of Combretastatin A-4 as a novel means of overcoming drug resistance associated with glucuronidation due to the expression of UGTs in the CA-4 resistant human colon cancer HT-29 cells. The alkene bridge of CA-4 is replaced with a β-lactam ring to circumvent potential isomerisation while the potential sites of glucuronate conjugation are deleted in the novel 3-substituted-1,4-diaryl-2-azetidinone analogues of CA-4. We hypothesise that glucuronidation of CA-4 is the mechanism of drug resistance in HT-29 cells. Ring B thioether containing 2-azetidinone analogues of CA-4 such as 4-(4-(methylthio)phenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (27) and 3-hydroxy-4-(4-(methylthio)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (45) were identified as the most potent inhibitors of tumour cell growth, independent of UGT status, displaying antiproliferative activity in the low nanomolar range. These compounds also disrupted the microtubular structure in MCF-7 and HT-29 cells, and caused G/M arrest and apoptosis. Taken together, these findings highlight the potential of chemical manipulation as a means of overcoming glucuronidation attributed drug resistance in CA-4 resistant human colon cancer HT-29 cells, allowing the development of therapeutically superior analogues.
尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）的葡萄糖醛酸化是癌细胞内在药物耐药性的一个原因。先前已经确定 Combretastatin A-4（CA-4）的葡萄糖醛酸化是肝癌细胞耐药的一种机制。在此，我们提出对 Combretastatin A-4 的β-内酰胺桥联类似物进行化学修饰，作为克服由于 CA-4 耐药的人结肠癌细胞 HT-29 中 UGTs 的表达而与葡萄糖醛酸化相关的耐药性的新方法。CA-4 的烯键被β-内酰胺环取代，以避免潜在的异构化，而在 CA-4 的新型 3-取代-1,4-二芳基-2-氮杂环丁酮类似物中删除了潜在的葡萄糖醛酸结合部位。我们假设 CA-4 的葡萄糖醛酸化是 HT-29 细胞耐药的机制。CA-4 的含 B 环硫醚的 2-氮杂环丁酮类似物，如 4-(4-(甲硫基)苯基）-3-苯基-1-(3,4,5-三甲氧基苯基）氮杂环丁-2-酮（27）和 3-羟基-4-(4-(甲硫基)苯基）-1-(3,4,5-三甲氧基苯基）氮杂环丁-2-酮（45）被鉴定为最有效的肿瘤细胞生长抑制剂，与 UGT 状态无关，在纳摩尔范围内显示出抗增殖活性。这些化合物还破坏了 MCF-7 和 HT-29 细胞的微管结构，并导致 G/M 期阻滞和细胞凋亡。综上所述，这些发现强调了化学修饰作为克服 CA-4 耐药的人结肠癌细胞 HT-29 中葡萄糖醛酸化归因的耐药性的潜在方法，允许开发治疗上更优越的类似物。
