Synthesis and Characterization of New Organometallic Benzo[b]thiophene Derivatives with Potential Antitumor Properties

摘要

The incorporation of organometallic rnoietics into the structure of known active drugs to improve their therapeutic properties has gained considerable interest in recent years. The benzo[b]thiophene derivative raloxifene is a selective estrogen receptor modulator (SERM) that has been found to decrease breast cancer risk in postmenopausal women compared to placebo. The current data suggest that, in the postmenopausal setting, raloxifene may have the benefits of the widely used tamoxifen with fewer side effects. As part of a program designed toward the synthesis and biological screening of organometallic benzo[b]thiophene derivatives inspired by the structure of raloxifene, we have prepared a series of 2-benzoyl-3-ferrocenylbenzo[b]thiophenes where the benzoyl substituent contains terminal tertiary alkylamino groups, expected to ensure affinity to the estrogen receptor. The synthetic strategy and full characterization (NMR, MS, X-ray diffraction, cyclic voltammetry) of the new ferrocenylbenzo[b]thiophenes is reported herein. Moreover, the new 2-benzoyl-3-ferrocenylbenzo[b]thiophene derivatives were tested for their cytotoxic properties against several human tumor cell lines. All the test compounds showed considerable cytotoxic activity; among these, [3-ferrocenyl-6-methoxybenzo[b]thiophen-2-yl][4-(piperazin-1-yl)metllylp henyl]methanone (compound 13) is of note, showing IC50 values in the low-micromolar range and more than I order of magnitude lower than those of the reference compound, cisplatin. In addition, chemosensitivity tests on resistant phenotypes indicated that compound 13 elicited no cross-resistance with cisplatin, besides not being a potential multidrug-resistant (MDR) substrate. Moreover, caspase-3 activation analyses revealed that 13 induced a caspase-3-dependent apoptotic cell-death mechanism. Taken together, these data suggest that the new 2-benzoyl-3-ferrocenylbenzo[b]thiophenes, in particular compound 13, have potentially useful antitumor properties.