Bismuth nitrate-induced novel nitration of estradiol: An entry to new anticancer agents

• An ecofriendly direct procedure for the nitration of estradiol is developed.
• Carbon linkers on the oxygen at C-3 with basic terminal moieties are introduced.
• Compounds 3 and 4 are cytotoxic for HepG2, Hepa1-6, Hep3B, HeLa and HT-29 cells.
• Compound 3 is more potent than 4-HT for both ER-positive and ER-negative cells.
• Compound 3 circumvented P-gp mediated drug resistance in ovarian cancer cells.

Direct nitration of estradiol was carried out using metal nitrates on solid surfaces under mild condition, and a combination of bismuth nitrate pentahydrate impregnated KSF clay was found to be the best reagent to synthesize 2- and 4-nitroestradiol effectively. Furthermore, various basic side chains were introduced, through O-linker at C-3, to these nitroestradiols. The ability of these derivatives to cause cytotoxicity in Estrogen Receptor (ER)-positive and ER-negative breast cancer cell lines, as well as cancer cell lines of other origins, was examined. Qualitative structure activity relationship (SAR) has also been studied. We found that a basic side chain containing either a piperidine or morpholine ring, when conjugated to 2-nitroestradiol, was particularly effective at causing cytotoxicity in each of the cancer cell lines examined. Surprisingly, this effective cytotoxicity was even seen in ER-negative breast cancer cells.

Figure optionsDownload as PowerPoint slide