Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone

• Published in: Bioorganic & medicinal chemistry 2017-02, Vol.25 (3), p.949-962
• Main Authors: Ivanov, Anton, Ejaz, Syeda Abida, Shah, Syed Jawad Ali, Ehlers, Peter, Villinger, Alexander, Frank, Eva, Schneider, Gyula, Wölfling, János, Rahman, Qamar, Iqbal, Jamshed, Langer, Peter
• Format: Article
• Language: English
• Subjects: Catalysis; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Estrone - chemical synthesis; Estrone - chemistry; Estrone - pharmacology; Humans; Lipase - antagonists & inhibitors; Lipase - metabolism; Molecular Structure; Pancreas - enzymology; Phosphatase inhibition; Stereoisomerism; Steroids; Structure-Activity Relationship; Suzuki reaction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.12.009

[Display omitted] Various novel arylated estrone derivatives, such as 2-aryl-, 4-aryl- and 2,4-diaryl-estrones, by Suzuki-Miyaura reactions. While the synthesis of 4-arylestrones could be carried out under standard conditions, the synthesis of 2-arylestrones and 2,4-diarylestrones required a thorough optimization of the conditions and it proved to be important to use sterically encumbered biaryl ligands. The best results were obtained by the use of RuPhos. Combination of developed Suzuki coupling reactions with subsequent cyclization reactions afforded more complex hybrid structures, containing dibenzofuran, benzocoumarin and steroid moieties. These derivatives were tested as pancreatic lipase inhibitors and it was found that most of the compounds exhibited inhibition of pancreatic lipase but the maximum inhibitory potential was shown by 4-arylestrones. All of the synthesized derivatives showed inhibitory values in the range of 0.82±0.01–59.7±3.12μM. The biological activity was also rationalized on the bases of docking studies.