Steroidal C-21 heteroaryl thioethers. Part 3: Pregn-4-eno-[3,2-c]pyrazole fused A ring modified steroids as selective glucocorticoid receptor modulators (dissociated steroids)

doi:10.1016/j.bmcl.2012.03.015

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 9, 1 May 2012, Pages 3291-3295

Dedicated to Professor Gilbert Stork on the occasion of his 90th birthday.

https://doi.org/10.1016/j.bmcl.2012.03.015 Get rights and content

Abstract

The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.

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Acknowledgments

We thank Dr. John C. Hunter, Dr. Malcom Maccoss, Dr. John Piwinski and Dr. William Greenlee from the Merck Research Laboratory for their support and guidance.

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Citation Excerpt :
HC is a common glucocorticoid drug, and has been extensively used for clinical treatment and animal husbandry owing to its various pharmacological activities of anti-inflammatory, antiviral, immunosuppression, anti-shock and regulating glucose metabolism [7]. In addition, HC also plays an important role in the production of drugs, usually as a key drug intermediate involved in the synthesis of multiple steroid hormone drugs [8]. As we all know, repeated washing, filtration, concentration and other unit operations are required to remove intermediates and by-products during the production of steroids, which will inevitably produce a large amount of HC residual pharmaceutical wastewater.
Hydrocortisone (HC), as a common steroid hormone drug, is also one of the key intermediates involved in the synthesis of multiple steroid hormone drugs. Residual HC in pharmaceutical wastewater frequently pollutes environmental water as steroid hormone contaminant and possesses great threat to human health as well as sustainable development of the ecosystem. Herein, in order to develop a highly efficient adsorbent system for selective enrichment and detection of HC in pharmaceutical wastewater, a novel amino-functionalized aluminum-based metal organic frameworks (Al-MOFs@NH₂) mesoporous nanorod is fabricated, in which 2-aminoterephthalic acid plays a dual role as organic linker and functional modification unit. The resultant Al-MOFs@NH₂ not only exhibits stable mesoporous structure but also has large specific surface area (849.76 m² g⁻¹) and plentiful binding sites, which significantly increases the adsorption capacity for HC. Under the promotion of hydrogen bonding and hydrophobic interaction together, Al-MOFs@NH₂ possesses high adsorption capacity (218.53 mg g⁻¹) for HC, as well as shows satisfactory selectivity for HC and other steroid hormones. Moreover, a method using Al-MOFs@NH₂ as solid phase extraction adsorbents combined with high performance liquid chromatography (HPLC) has been developed to specifically enrich and detect trace amount of HC in pharmaceutical wastewater. The developed method has a low limit of detection (LOD) (0.5 $\times$ 10⁻³ μg mL⁻¹) and shows satisfactory recoveries for HC (75.9%−102.5%) with an acceptable relative standard deviation (RSD). These results demonstrate that the facile one-step preparation and excellent adsorption capacity makes Al-MOFs@NH₂ attractive to capture and remove environmental steroid hormone pollutants. More importantly, the method proposed in this work is expected to provide a prospective solution for analysis of strong bioactive contaminants in pharmaceutical wastewater.
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Steroidal C-21 heteroaryl thioethers. Part 3: Pregn-4-eno-[3,2-c]pyrazole fused A ring modified steroids as selective glucocorticoid receptor modulators (dissociated steroids)

Abstract

Graphical abstract

Section snippets

Acknowledgments

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

J. Med. Chem.

Gazz. Chim. Ital.

J. Am. Chem. Soc.