Abstract
In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent aromatase inhibitors. First, these compounds were tested for their anti-cancer properties against human breast cancer cell line (MCF-7). The most active compounds 5c, 5e, 5k, and 5m on MCF-7 cell line were subject to further in vitro aromatase enzyme inhibition assays to determine the possible mechanisms of action underlying their activity. Compound 5e showed slight less potent aromatase inhibitory activity than that of letrozole with IC50 = 0.032 ± 0.042 µM, compared to IC50 = 0.024 ± 0.001 µM for letrozole. Furthermore, compound 5e and reference drug letrozole were docked into human placental aromatase enzyme to predict their possible binding modes with the enzyme. Finally, ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds (5a–5p) were calculated by QikProp 4.8 software.
Highlights
Aromatase is a member of the cytochrome P450 enzyme that catalyzes the biosynthesis of estrogens from androgens [1,2]
Synthesis of the target compounds was accomplished according to the steps illustrated in Scheme 1
The reaction of compound 3a, 3b with hydrazine hydrate in the presence of ethanol produced compounds 4a, 4b
Summary
Aromatase is a member of the cytochrome P450 enzyme that catalyzes the biosynthesis of estrogens from androgens [1,2]. Estrogen levels have been shown to be higher in breast cancer cells. Inhibition of aromatase is one of the effective current therapeutic strategies for controlling estrogen-dependent breast cancer. One of the commonly used classes of drugs for the management of estrogen-dependent cancer is aromatase inhibitors (AIs) [1,3,4]. Aminoglutethimide is the prototype nonsteroidal inhibitor of aromatase. Problems with the side effects and selectivity of aminoglutethimide led to the development of the second-generation of nonsteroidal aromatase inhibitor (Fadrazole bearing imidazole structure) [7].
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