Design, Synthesis, Antitumor Mechanism And Structure-Activity Relationships Of WB852 Analogues

A large number of natural diterpenes and sesquiterpenes have remarkable bioactivity. The presence of α-methylene cyclopentanone appearing in diterpenes and α-methylene-γ-lactones appearing in sesquiterpenes plays a significant r ole for anti-tumour and cytotoxic activities. Inspired by the anti-tumour effect of these natural components we designed and synthesized a series of 2-alkylaminomethyl-5-(E)-alkylidene cyclopentanone hydrochlorides. WB852, one of the representatives of such compounds, had significant anti-tumor activities in vitro and in vivo and was an effective apoptosis-inducing agent in leukemia cells and it decreased intracellular reduced glutathione (GSH) of leukemia cells. The mass spectrum of a GSH adduct of WB852 indicated that the mechanism of action for WB852 and its analogues may proceed via an elimination-Michael addition process to form an α-methylene group, followed by a 1,4-Michael addition with free cysteine sulfhydryl groups including GSH to form thiol-addition product. GSH plays an important role in cells to prevent cell death as a substrate of glutathione-s-transferases (GST) which involve in the drug resistance. Among the GST family it has been found that GSTπ was increased in chemotherapy-resistance cancer cells and thus GSTπ could be used as a potential target for the cancer treatment. The potential GSH binding ability of WB852 suggests that it may inhibit GSTπ activity directly or indirectly, and would be potent anticancer agents in tumor cells even with higher GSTπ activity. WB852 as a promising lead compound was supposed to induce tumor cells apoptosis through binding cellular GSH, inhibiting GSTπ activity, decreasing intracellular GSH and generation of oxidative stress.Based on the structure-activity relationships (SAR) of antitumor activities of cyclopentanone Mannich base hydrochlorides summarized previously, with WB852 as a lead compound, modified systemically from the following three aspects of WB852: alkylaminomethyl, alkylidene and ketone group for further study of the SAR, three types of...