β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells.

摘要: Glucuronidation by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) is a cause of intrinsic drug resistance in cancer cells. combretastatin A-4 (CA-4) was previously identified as mechanism hepatocellular Herein, we propose chemical manipulation β-lactam bridged analogues Combretastatin novel means overcoming associated with glucuronidation due to the expression UGTs CA-4 resistant human colon HT-29 cells. The alkene bridge replaced ring circumvent potential isomerisation while sites glucuronate conjugation are deleted 3-substituted-1,4-diaryl-2-azetidinone CA-4. We hypothesise that Ring B thioether containing 2-azetidinone such 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 most potent inhibitors tumour cell growth, independent UGT status, displaying antiproliferative activity low nanomolar range. These compounds also disrupted microtubular structure MCF-7 HT-29 cells, caused G2/M arrest apoptosis. Taken together, these findings highlight attributed allowing development therapeutically superior analogues.