ABSTRACT

Calculated structures and energies of ketenes RCH=C==O (R = H, Li, CH=C=O) at the 6-31G5/6-31G* level reveal major stabilization by electropositive groups and destabilization by electronegative substituents. There is a good correlation of substituent stabilization of ketenes defined by AE for the isodesmic reaction RCH=C=O + CH3CH=CH2 -CH,CH=C=O + RCH=CH2 and group electronegativities xBE reported by Boyd and Edgecombe. Thus the primary stabilizing influence of substituents on ketenes is evidently by a-electron donation to the electronegative ketene moiety. There is also evidence that substituents stabilize ketenes by A withdrawal and destabilize ketenes by n-r donation. The calculated substituent effects on ketenes are compared to known experimental results and to the corresponding effects on allenes and on /3-ethyl carbocations. Because of the fascinating electronic structure of ketenes these species have frequently been the subject of investigation by molecular orbital (MO) methods.l+ These studies have focussed on the electronic structure of ketene itself,2 the reaction of ketenes with p r o t~n s l~,~ and nucleophiles,Ib cycloaddition of ketenes with alkene^^^-^*^,^ and dialkoxyalkynes? and rearrangements of conjugated k e t e n e~.~g ?~ Many substituted ketenes have been generated and their properties o b~e r v e d ,~~-~ and while it is clear that bulky groups (1) (a) Presented in part as a preliminary communication: Allen, A. D.; Gong, L.; Tidwell, T. T. Hadad, C. M.; Breneman, C. M.; Laidig, K. E.; Murcko, M. A,; LePage, T.(7) (a) Rosenstock, H. M.; Draxl, K.; Steiner, B. W.; Herron, J. T.

BACKGROUND AND PURPOSEIt is thought that the anti-inflammatory effects of glucocorticoids (GCs) are largely due to GC receptor (GR)-mediated transrepression of NF-kB and other transcription factors, whereas side effects are caused by activation of gene expression (transactivation). Selective GR modulators (SGRMs) that preferentially promote transrepression should retain anti-inflammatory properties whilst causing fewer side effects. Contradicting this model, we found that anti-inflammatory effects of the classical GC dexamethasone were partly dependent on transactivation of the dual specificity phosphatase 1 (DUSP1) gene. We wished to determine whether anti-inflammatory effects of SGRMs are also mediated by DUSP1. EXPERIMENTAL APPROACHDissociated properties of two SGRMs were confirmed using GR-and NF-kB-dependent reporters, and capacity to activate GC-responsive elements of the DUSP1 gene was tested. Effects of SGRMs on the expression of DUSP1 and pro-inflammatory gene products were assessed in various cell lines and in primary murine Dusp1 +/+ and Dusp1 -/-macrophages. KEY RESULTSThe SGRMs were able to up-regulate DUSP1 in several cell types, and this response correlated with the ability of the compounds to suppress COX-2 expression. Several anti-inflammatory effects of SGRMs were ablated or significantly impaired in Dusp1 -/-macrophages. CONCLUSIONS AND IMPLICATIONSLike dexamethasone, SGRMs appear to exert anti-inflammatory effects partly via the up-regulation of DUSP1. This finding has implications for how potentially therapeutic novel GR ligands are identified and assessed. AbbreviationsAP-1, activating protein 1; BMM, bone marrow-derived macrophage; CXCL1, chemokine (CXC motif) ligand 1; dex, dexamethasone; DUSP1, dual specificity phosphatase

No abstract

No abstract