RESUMEN
Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.
Asunto(s)
Antineoplásicos , Ácidos Cafeicos , Alcohol Feniletílico , Humanos , Ácidos Cafeicos/farmacología , Ácidos Cafeicos/química , Ácidos Cafeicos/síntesis química , Células HeLa , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacología , Alcohol Feniletílico/química , Alcohol Feniletílico/síntesis química , Agua/química , Línea Celular Tumoral , Amidas/farmacología , Amidas/química , Supervivencia Celular/efectos de los fármacosRESUMEN
Plant polyphenols, such as the African potato (Hypoxis hemerocallidea)-derived bis-catechol rooperol, can display promising anticancer activity yet suffer from rapid metabolism. Embarking upon a program to systematically examine potentially more metabolically stable replacements for the catechol rings in rooperol, we report here a general, scalable synthesis of rooperol and analogues that builds on our previous synthetic approach incorporating a key Pd-catalyzed decarboxylative coupling strategy. Using this approach, we have prepared and evaluated the cancer cell cytotoxicity of rooperol and a series of analogues. While none of the analogues examined here were superior to rooperol in preventing the growth of cancer cells, analogues containing phenol or methylenedioxyphenyl replacements for one or both catechol rings were nearly as effective as rooperol.