A-Ring-Substituted Estrogen-3-O-sulfamates:  Potent Multitargeted Anticancer Agents

Efficient and flexible syntheses of 2-substituted estrone, estradiol and their 3-O-sulfamate (EMATE) derivatives have been developed using directed ortho-lithiation methodology. 2-Substituted EMATEs display a similar antiproliferative activity profile to the corresponding estradiols against a range of human cancer cell lines. 2-Methoxy (<BO>3</BO>, <BO>4</BO>), 2-methylsulfanyl (<BO>20</BO>, <BO>21</BO>) and 2-ethyl EMATEs (<BO>32</BO>, <BO>33</BO>) proved the most active compounds with 2-ethylestradiol-3-O-sulfamate (<BO>33</BO>), displaying a mean activity over the NCI 55 cell line panel 80-fold greater than the established anticancer agent 2-methoxyestradiol (<BO>2</BO>). 2-Ethylestradiol-3-O-sulfamate (<BO>33</BO>) was also an effective inhibitor of angiogenesis using three in vitro markers, and various 2-substituted EMATEs also proved to be inhibitors of steroid sulfatase (STS), a therapeutic target for the treatment of hormone-dependent breast cancer. The potential of this novel class of multimechanism anticancer agents was confirmed in vivo with good activity observed in the NCI hollow fiber assay and in a MDA-MB-435 xenograft mouse model.