Abstract
A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-β-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced ≥62% HSD1 inhibition at 5 µM and, furthermore, three of them produced ≥68% inhibition at 1 µM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-β-hydroxysteroid dehydrogenase 2 – a requirement for lowering effective oestradiol levels in vivo. Moreover, the analysis led to the synthesis and discovery of 3-imidazolecoumarin as a potent aromatase inhibitor. In short, coumarin core can be tailored with specific ring and polar moiety substitutions to block either the sulphatase pathway or the aromatase pathway for treating breast cancer and endometriosis.
Highlights
Despite the recent advances made in early tumour detection, clinical treatments and avoidance of menopausal hormone therapies, breast cancer continues to be the most common invasive cancer, and a second leading cause of cancer death for women[1]
All reactions were monitored by thin layer chromatography (TLC) on silica gel plates. 1H NMR and 13C NMR data were recorded on a Bruker Avance 400 MHz spectrometer or Bruker Avance III 300 MHz spectrometer (Bruker, Billerica, MA)
Whether the small-molecule design originates from automated virtual screening schemes, expert de novo work[33] or combination of the two, the computer-aided drug discovery (CADD) requires experimental verification[14,34]. This is achieved by pairing biochemical activity testing with, for example X-ray crystallographic studies[35], site-directed mutagenesis experiments[36,37], and/or “mutating” the lead compounds into diverse libraries of closely-related analogues using organic synthesis[38,39,40]
Summary
Despite the recent advances made in early tumour detection, clinical treatments and avoidance of menopausal hormone therapies, breast cancer continues to be the most common invasive cancer, and a second leading cause of cancer death for women[1]. The aromatase pathway (active in local E2 production) is in a lesser role with most breast cancers[2], widely used drugs, such as anastrozole focus on blocking it instead of the more prominent sulphatase pathway. A vast number of steroidal (8–10; e.g. E2B in Figure 1(C)) and non-steroidal (see e.g.11–13) compounds are known to inhibit the HSD1 activity, but none of these promising leads has passed clinical trials so far. The 3-phenylcoumarin analogues 1–7 produce HSD1 inhibition at a varying degree, but 8 and 9 were found to be inactive (Table 1). Compound 10 or 3-imidazolecoumarin inhibit aromatase instead of HSD1. The coumarin-based compounds have potential for lowering E2 levels needed in battle against diseases, such as breast cancer or endometriosis by blocking either the aromatase pathway or the sulphatase pathway
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