Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL, 32224, USA.
Department of Chemistry and Biochemistry, Kent State University, Kent, OH, 44242, USA.
ChemMedChem. 2019 Jun 18;14(12):1173-1184. doi: 10.1002/cmdc.201900179. Epub 2019 May 14.
A series of deuterated curcuminoids (CUR) were synthesized, bearing two to six OCD groups, in some cases in combination with methoxy groups, and in others together with fluorine or chlorine atoms. A model ring-deuterated hexamethoxy-CUR-BF and its corresponding CUR compound were also synthesized from a 2,4,6-trimethoxybenzaldehyde-3,5-d precursor. As with their protio analogues, the deuterated compounds were found to remain exclusively in the enolic form. The antiproliferative activities of these compounds were studied by in vitro bioassays against a panel of 60 cancer cell lines, and more specifically in human colorectal cancer (CRC) cells (HCT116, HT29, DLD-1, RKO, SW837, and Caco2) and in normal colon cells (CCD841CoN). The deuterated CUR-BF adducts exhibited better overall growth inhibition by NCI-60 assay, while for other CUR-BF adducts the non-deuterated analogues were more cytotoxic. Results of the more focused comparative cell viability assays followed the same trend, but with some variation depending on cell lines. The CUR-BF adducts exhibited significantly higher cytotoxicity than CURs. Structural studies (X-ray and DFT) and computational molecular docking calculations comparing their inhibitory efficacy with those of known anticancer agents used in chemotherapy are also reported.
一系列氘代姜黄素（CUR）被合成，带有两个到六个 OCD 基团，在某些情况下与甲氧基结合，在其他情况下与氟或氯原子结合。还从 2,4,6-三甲氧基苯甲醛-3,5-二前体合成了模型环氘代六甲氧基-CUR-BF 及其相应的 CUR 化合物。与它们的原代类似物一样，氘代化合物被发现仍然完全处于烯醇形式。通过体外生物测定法对 60 种癌细胞系进行了这些化合物的抗增殖活性研究，特别是在人结直肠癌细胞（HCT116、HT29、DLD-1、RKO、SW837 和 Caco2）和正常结肠细胞（CCD841CoN）中。与 NCI-60 测定相比，氘代 CUR-BF 加合物表现出更好的整体生长抑制作用，而对于其他 CUR-BF 加合物，非氘代类似物的细胞毒性更强。更集中的比较细胞活力测定的结果遵循相同的趋势，但根据细胞系的不同而有所变化。与 CUR 相比，CUR-BF 加合物表现出更高的细胞毒性。还报告了结构研究（X 射线和 DFT）和计算分子对接计算，比较了它们与化疗中使用的已知抗癌药物的抑制效果。
