Synthesis of Tamoxifen‐Artemisinin and Estrogen‐Artemisinin Hybrids Highly Potent Against Breast and Prostate Cancer

In the search for new and effective treatments of breast and prostate cancer, a series of hybrid compounds based on tamoxifen, estrogens, and artemisinin were successfully synthesized and analyzed for their in vitro activities against human prostate (PC-3) and breast cancer (MCF-7) cell lines. Most of the hybrid compounds exhibit a strong anticancer activity against both cancer cell lines - for example, EC50 (PC-3) down to 1.07 μM, and EC50 (MCF-7) down to 2.08 μM - thus showing higher activities than their parent compounds 4-hydroxytamoxifen (afimoxifene, 7; EC50 =75.1 (PC-3) and 19.3 μM (MCF-7)), dihydroartemisinin (2; EC50 =263.6 (PC-3) and 49.3 μM (MCF-7)), and artesunic acid (3; EC50 =195.1 (PC-3) and 32.0 μM (MCF-7)). The most potent compounds were the estrogen-artemisinin hybrids 27 and 28 (EC50 =1.18 and 1.07 μM, respectively) against prostate cancer, and hybrid 23 (EC50 =2.08 μM) against breast cancer. These findings demonstrate the high potential of hybridization of artemisinin and estrogens to further improve their anticancer activities and to produce synergistic effects between linked pharmacophores.