Synthesis of a glucose conjugate of pristimerin and evaluation of its anticancer activity

Taking advantage of the Warburg effect in cancer cells, glucose conjugation has emerged as a useful strategy for targeted delivery of anticancer agents. Pristimerin is a naturally occurring triterpenoid that displays potent but non-selective cytotoxicity. We developed a convergent and modular approach to con-struction of glucose -payload conjugates featuring copper-mediated azide -alkyne cycloaddition and pre-pared a glucose conjugate of pristimerin through this approach. The anticancer activity of this conjugate was evaluated in cancer cells and normal cells; however, the selectivity toward cancer cells was not sig-nificantly improved. We then examined the extracellular stability of the conjugate and found that its ester linkage was cleaved rapidly in Dulbecco's Modified Eagle's Medium at 37 degrees C, which resulted in the release of pristimerin. In fact, the inorganic components in this medium were sufficient to induce the cleavage. Given that the subtle difference between intrinsic stability and extracellular stability of the conjugate linker is often underappreciated, this work highlights the importance of the latter in the development of target-selective conjugates.(c) 2022 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.