Abstract
A series of novel conjugates of camptothecin and 5-fluorouracil were first synthesized and their cytotoxic activities against two human tumor cell lines (SGC-7901 and A-549) as well as in vitro pharmacokinetic determination of lactone stability were studied. Among these compounds, most tested conjugates showed comparable or superior cytotoxic activities to 2, but less potent compared with 1. Particularly, conjugates 10b and 10d were highly active against A-549 with IC50 values of 0.45 and 0.38 µmol L-1, respectively. Also, the in vitro pharmacokinetic determination of lactone levels of representative compound 10b showed that the biological life span of their lactone forms in human and mouse plasma significantly increased compared with their mother compound 1. Quantitative structure-activity relationship (QSAR) method was then applied for developing linear models to predict the cytotoxic activities of these derivatives that have not yet been synthesized or experimentally tested. In addition, molecular docking was used to clarify the binding mode of these derivatives to human DNA topoisomerase I. The important hydrogen-bonding interactions were observed between these derivatives and their receptor. The results from molecular modeling and QSAR study can guide the design of novel conjugates with higher antitumor activity.
Highlights
A challenging research focus in current cancer therapy is the discovery of molecules that could be selective for tumor cells and that could be characterized by reduced undesirable effects
We firstly synthesized a series of novel conjugates of camptothecin and 5-fluorouracil joined by dipeptide linkages based on the effective combination principle
Conjugates 10b and 10d were highly active against A-549 with IC50 values of 0.45 and 0.38 μmol L-1 respectively
Summary
A challenging research focus in current cancer therapy is the discovery of molecules that could be selective for tumor cells and that could be characterized by reduced undesirable effects. Included in approaches to improving the biological profile of CPTs are the development of prodrugs for preferential cellular uptake into tumor cells, enhanced solubility and lipophilicity, and stabilization of the camptothecin E-ring lactone. These efforts have led to the food and drug administration (FDA) approval of topotecan (2) and irinotecan (3) for colon and ovarian cancers treatment, respectively, and to the synthesis of several novel CPT derivatives that are currently in various stages of clinical trials.[11,12,13]
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