Discovery of novel pterostilbene/biphenyl tethered 5-FU based conjugates targeting colorectal cancer: synthesis, cytotoxic and ADMET modeling studies

Abstract

A new series of conjugates linking 5-FU with parts of pterostilbene and biphenyl were designed, and synthesized, besides, their biological activity was assessed against human colorectal adenocarcinoma cells (SW480) and the non-malignant cell line NCM460. Novel conjugates were first screened to establish the potential at 100 µM single dose, finding two active compounds 5e and 5g that caused more than 70% inhibition. In addition, in the seven-dose screening it was observed that, although both compounds were more active than the starting molecule 3, only compound 5e was more selective toward cancer cells than the drug 5-fluorouracil (5-FU). A theoretical examination of pharmacokinetics, toxicological, and drug-like characteristics indicates that the most promising hybrid 5e, has a strong potential to progress to further preclinical studies. Our findings unequivocally showed the effectiveness of 5-FU/pterostilbene hybrids, with the 3,4,5-trimethoxyphenylsubstituted compound serving as a prototype molecule for upcoming studies that focus on new methods for treating colorectal cancer.