Novel steroid spiro enones: condensation of prednisolone derivatives with diethyl oxalate.
In a continuing effort to discover potent anti-inflammatory steroids without systemic side effects, diethyl oxalate was condensed with the 17beta-ketol side chain of prednisolone derivatives. Prednisolone gave the most interesting result in forming a novel spiro enone with alpha-hydroxy and beta-carboxylic ester substitutions, and a facile one-pot procedure has been established for the synthesis of this highly functionalized spiro enone structure. The spiro products were tested for their binding potency to the RAW 264.7 macrophage glucocorticoid receptor, for their effect on LPS-induced nitric oxide generation in RAW 264.7 cells, and for their inhibition of rats ear edema induced by croton oil. The new compounds showed weak activities in all of the bioassays. Because the corresponding acid metabolites of two representative spiro enone esters gave no activity in either the binding assay or the nitric oxide generation test, the novel steroids are probably antedrugs. The reduced potency as compared to their parent compounds suggests that the rigid spiro structure is unfavorable to anti-inflammatory activities. Molecular modeling studies confirm that the spiro enones adopt a rigid planar geometry with the ester group in the plane.
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College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee 32307, USA. hlee@famu.edu
Heiman
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Chen
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Lee
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D000818:Animals; D002460:Cell Line; D003369:Cottonseed Oil / Q000009:adverse effects; D004423:Ear; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D008264:Macrophages / Q000737:chemistry; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II; D010070:Oxalates / Q000737:chemistry; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D020033:Protein Isoforms / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use*
D003369:Cottonseed Oil; D010070:Oxalates; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D013141:Spiro Compounds; D009569:Nitric Oxide; D011239:Prednisolone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat