Journal article
Deacylcortivazol-like pyrazole regioisomers reveal a more accommodating expanded binding pocket for the glucocorticoid receptor
RSC medicinal chemistry, Vol.12(2), pp.23-212
02/01/2021
DOI: 10.1039/d0md00278j
PMCID: PMC8127617
PMID: 34046609
Abstract
Glucocorticoids (GCs) are widely used, potent anti-inflammatory and chemotherapeutic drugs. They work by binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor, inducing translocation to the nucleus and regulation of genes that influence a variety of cellular activities. Despite being effective for a broad number of conditions, GC use is limited by severe side effects. To identify ligands that are more selective, we synthesized pairs of regioisomers in the pyrazole ring that probe the expanded binding pocket of GR opened by deacylcortivazol (DAC). Using an Ullmann-type reaction, a deacylcortivazol-like (DAC-like) backbone was modified with five pendant groups at the 1 '- and 2 '-positions of the pyrazole ring, yielding 9 ligands. Most of the compounds were cytotoxic to leukemia cells, and all required GR expression. Both aliphatic and other aromatic groups substituted at the 2 '-position produced ligands with GC activity, with phenyl and 4-fluorophenyl substitutions exhibiting high cellular affinity for the receptor and >5x greater potency than dexamethasone, a commonly used strong GC. Surprisingly, phenyl substitution at the 1 '-position produced a high-affinity ligand with similar to 10x greater potency than dexamethasone, despite little apparent room in the expanded binding pocket to accommodate 1 '-modifications. Other 1 '-modifications, however, were markedly less potent. The potency of the 2 '-substituted and 1 '-substituted DAC-like compounds tracked linearly with cellular affinity but had different slopes, suggesting a different mode of interaction with GR. These data provide evidence that the expanded binding pocket opened by deacylcortivazol is more accommodating that expected, allowing development of new, and possibly selective, GCs by substitution within the pyrazole ring.
Details
- Title: Subtitle
- Deacylcortivazol-like pyrazole regioisomers reveal a more accommodating expanded binding pocket for the glucocorticoid receptor
- Creators
- Jessica A. O. Zimmerman - Roy J. and Lucille A. Carver College of MedicineMimi Fang - Roy J. and Lucille A. Carver College of MedicineBintou Doumbia - Butler UniversityAlexis Neyman - Butler UniversityJi Hyeon Cha - Butler UniversityMichael Thomas - Butler UniversityBonnie Hall - Grand View UniversityMeng Wu - High Throughput BiologyAnne M. Wilson - Butler UniversityMiles A. Pufall - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- RSC medicinal chemistry, Vol.12(2), pp.23-212
- Publisher
- Royal Soc Chemistry
- DOI
- 10.1039/d0md00278j
- PMID
- 34046609
- PMCID
- PMC8127617
- ISSN
- 2632-8682
- eISSN
- 2632-8682
- Number of pages
- 11
- Grant note
- R50CA243786-01; P30CA086862; S10 RR029274 / UIHTS Core MCB-1552862 / National Science Foundation CAREER grant; National Science Foundation (NSF)
- Language
- English
- Date published
- 02/01/2021
- Academic Unit
- Pharmacy; Stead Family Department of Pediatrics; Hematology/Oncology; Biochemistry and Molecular Biology
- Record Identifier
- 9984293089702771
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