Tamoxifen (TAM) has been prescribed worldwide to patients with and women at high-risk of breast cancer. However, long-term use of TAM increases the incidence of endometrial cancer. The carcinogenic mechanisms of TAM have been extensively investigated. TAM is hydroxylated and sulfonated at α-carbon to form α-hydroxytamoxifen-O-sulfonate. This metabolite readily reacts with genomic DNA, particularly with 2'-deoxyguanosine, leading to DNA replication error. TAM also exerts estrogenic activity at endometrial tissue to induce endometrial hyperplasia. Therefore, our efforts focused on the development of novel and safer anti-estrogens to diminish carcinogenic potential of TAM based on chemical modifications. In this review, we describe a crucial idea of our drug design and introduce our compounds SS1020 and SS5020, possessing high effectiveness, and no genotoxic and estrogenic activities.
Keywords: Anti-breast cancer agent; Cancer chemoprevention; Cancer therapy; Coactivator; DNA adduct formation; Endometrial cancer; Estrogen receptor; Metabolic activation; Tamoxifen.