The effect of an estrone D-lactam steroid ester derivative on breast cancer cells and its predicted binding interactions with the ligand binding domain of estrogen receptor-alpha.

In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL). The aim of this study was to investigate the in vitro activity of ESBL against primary breast carcinoma (BC) cells of operable tumors in comparison with CBL. Cells derived from fresh tumor sections that were obtained from 28 postmenopausal women with ductal BC were treated with CBL and ESBL. Apoptotic cells were distinguished from viable ones with flow cytometric methods. ESBL generated a significantly higher rate of cell apoptosis and cytotoxicity than CBL. ESBL cytotoxic effect demonstrated a significant positive weak to moderate dose-dependent correlation with the ER expression. ESBL produced antineoplastic activity superior to CBL on primary BC tumors in vitro. Moreover, a docking study on the binding interactions of ESBL with the ligand binding domain (LBD) of estrogen receptor-alpha (ERalpha) was investigated. ESBL was found to be positioned inside the binding cavity with its steroidal moiety, whereas the alkylating moiety protruded out of receptor's pocket.