Design, synthesis, and biological evaluation of indole-modified tamoxifen relatives as potent anticancer agents

Modulation of existing drugs is an attractive strategy to achieve improved activity in cancer therapy by lowering their effective dose. Preparation of relatives has been suggested and explored to improve the therapeutic effect of anticancer agents. In the current study, we attempted to modulate tamoxifen (TMX) by replacing the C-phenyl ring in its backbone with an indole or oxindole. In addition, it was possible to convert indole-modified tamoxifens to the corresponding 3,3'-bis(indolyl)methanes (BIMs) via an electrophilic substitution reaction with various benzaldehydes. We analyzed the anticancer potential of these indole-modified tamoxifens against various breast cancer cell lines and identified certain tamoxifen relatives with the potential to treat estrogen receptor (ER)-positive breast cancers, based on preliminary results of cell viability and caspase activity assays. The indole-modified tamoxifen BIM-Z,Z-35b, BIM-Z,Z-35f, and E-33 selectively reduced the viability of receptor-sensitive breast cancer cells more effectively than tamoxifen and suppressed the expression of ER-regulated genes. Moreover, Caspase-8 activity showed a specific increase in MCF-7 cells treated with these compounds. Our results indicate that these compounds may be an alternative to tamoxifen for the treatment of breast cancer.