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

Abstract

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, EC 50 (PC‐3) down to 1.07 μM, and EC 50 (MCF‐7) down to 2.08 μM – thus showing higher activities than their parent compounds 4‐hydroxytamoxifen (afimoxifene, 7 ; EC 50 =75.1 (PC‐3) and 19.3 μM (MCF‐7)), dihydroartemisinin ( 2 ; EC 50 =263.6 (PC‐3) and 49.3 μM (MCF‐7)), and artesunic acid ( 3 ; EC 50 =195.1 (PC‐3) and 32.0 μM (MCF‐7)). The most potent compounds were the estrogen‐artemisinin hybrids 27 and 28 (EC 50 =1.18 and 1.07 μM, respectively) against prostate cancer, and hybrid 23 (EC 50 =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.

Antimalarial and anticancer properties of artesunate and other artemisinins: current development

“…Besides antimalarial activity, artesunate, other artemisinins, and ART-hybrid also possess profound cytotoxic activity against tumor cells [42][43][44][45][46][47]. Recently, Li et al reviewed a paper about artemisinins against hematological malignancies [48].…”

Artemisinins as a novel anti-cancer therapy: Targeting a global cancer pandemic through drug repurposing

“…Tumour-promoting inflammation is also induced by chemical and environmental human carcinogens, such as tobacco, alcohol, asbestos, aflatoxins and nitrosamines. It is increasingly recognized that these carcinogens can also block the resolution of inflammation resulting in cancer development and progression ( Feng et al, 2014 ; Fröhlich et al, 2020 ; Hu, Chen, Zhang, Lou, & Zhou, 2014 ).…”

“…Artesunate has also shown ability to restore sensitivity of castrate resistant prostate cancer cell lines and mouse models to anti-androgen therapy ( Nunes et al, 2017 ). Tamoxifen–artemisinin and estradiol-artemisinin based hybrids have also shown anticancer activity against breast and prostate cancer cell lines ( Fröhlich et al, 2020 ). Artemisinin compounds have displayed anticancer activity in cancer cell lines resistant to conventional chemotherapies such as doxorubicin, hydroxyurea and methotrexate without developing cross resistance ( Feng et al, 2014 ).…”

Artemisinins as Anticancer Drugs: Novel Therapeutic Approaches, Molecular Mechanisms, and Clinical Trials

“…Enhance anticancer activity (Fröhlich et al, 2020) ARTs with chemotherapeutics or phytochemicals have been highlighted in recent years ( Table 3). These findings provided promising therapeutic approaches for cancer therapy.…”

“…Furthermore, the poor solubility of ARTs as well as a short half-life and low bioavailability upon oral administration lead to urgent needs for the finding of novel chemical structures to solve these problems ( Crespo-Ortiz and Wei, 2012 ; Li et al, 2016 ). To overcome these drawbacks, some novel chemical structures of ARTs have been developed as cancer candidates including mitochondria-targeted derivatives and hybrids while new therapeutic approaches of novel nano-formulations and combination therapy were explored as well ( Zhang X. et al, 2015 ; Zhang et al, 2016 ; Gao et al, 2018 ; Suraweera et al, 2018 ; Hu et al, 2019 ; Nosrati et al, 2019 ; Wang Y. et al, 2019 ; Fröhlich et al, 2020 ; Zhang et al, 2020 ).…”