Abstract
In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1H-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate 3L demonstrated the highest activity in the enzymatic assay inhibiting the STS activity to 7.98% at 0.5 µM concentration. Furthermore, to verify whether the obtained STS inhibitors are able to pass through the cellular membrane effectively, cell line experiments have been carried out. We found that the lowest STS activities were measured in the presence of compound 3L (remaining STS activity of 5.22%, 27.48% and 99.0% at 100, 10 and 1 nM concentrations, respectively). The measured STS activities for Irosustat (used as a reference) were 5.72%, 12.93% and 16.83% in the same concentration range. Moreover, a determined IC50 value of 15.97 nM for 3L showed that this compound is a very promising candidate for further preclinical investigations.
Highlights
IntroductionAs reported by International Agency for Research on Cancer, there were more than 18 million new cases diagnosed and 9.5 million tumour-related deaths in 2018 worldwide[1]
Cancer is the second leading cause of death worldwide
Current breast cancer therapies are based on chemotherapeutics that act as selective oestrogen receptor modulators (SERMs) (e.g. Tamoxifen) or inhibitors of the aromatase enzyme complex (e.g. Letrozole or Anastrozole)[8,9,10]
Summary
As reported by International Agency for Research on Cancer, there were more than 18 million new cases diagnosed and 9.5 million tumour-related deaths in 2018 worldwide[1]. 95% of breast cancer cases in the primary stage are hormone-sensitive, and biological active hormones (including oestrogens and androgens) play a crucial role in the proliferation of tumours cells[3]. Current breast cancer therapies are based on chemotherapeutics that act as selective oestrogen receptor modulators (SERMs) (e.g. Tamoxifen) or inhibitors of the aromatase enzyme complex (e.g. Letrozole or Anastrozole)[8,9,10]. There are studies demonstrating a significant increment of STS and 17bHSD1 following aromatase inhibitor therapy of ER positive postmenopausal breast carcinoma patients due to the compensatory response of breast carcinoma tissues to oestrogen depletion[12]
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