Synthesis and preliminary evaluation of estradiol diselenocyanate derivatives as potential antitumor agents

Cancer is a prominent disease that poses a significant threat to human health, and the exploration of highly efficient and low-toxicity anticancer drugs remains an active area of research. Leveraging the cell-penetrating and binding capabilities of steroids, along with the multifunctional pharmacological properties of selenocyano groups, novel compounds are being designed and synthesized with the aim of discovering highly efficient and minimally toxic anti-tumor drugs. In the present study, two selenocyano pharmacophores were incorporated into estradiol to synthesize a series of estradiol diselenocyanate derivatives with a 3-selenocyanoalkoxy-17-selenocyanoester structure. The results of antiproliferative activities evaluation demonstrated that the estradiol derivatives with 3-selenocyanobutoxy moiety exhibited potent inhibitory activity against tumor cell proliferation, especially for triple negative breast cancer cell line MDA-MB-231. Their antiproliferative efficacy was significantly superior to that of estradiol analogues with 3-selenocyanooctyloxy and corresponding monoselenocyanate precursors, indicating a synergistic effect upon introduction of the second selenocyano group on cytotoxicity. The IC₅₀ values for compound 4g against HeLa, HepG-2, and MCF-7 cells were determined as 3.20, 3.17, and 5.41 μM respectively; notably lower than those observed for its corresponding monoselenocyano precursor 3g which showed IC₅₀ values of 15.12, 16.09, and 9.44 μM, respectively. Remarkably, the IC₅₀ of compound 4e against MDA-MB-231 cells is only 5.04 μM and exhibited significant inhibitory activity against MDA-MB-231 zebrafish xenograft tumors. The inhibition of these compounds on tumor cell proliferation was attributed to induction of apoptosis in these cells. Thus, the estradiol diselenocyanate compounds investigated herein hold great potential as novel antitumor drugs, and warrant further investigation.