Anti-inflammatory effects of butadiene Diels-Alder adducts to some 1-dehydroglucocorticoids in rats.

Three compounds (C1, C2 and C3) were synthesized by reacting dexamethasone as a strong anti-inflammatory drug or prednisolone as a moderate one with 1,3-butadiene under Diels-Alder reaction conditions to produce pentacyclic compounds. The structures of C1 [(11 beta,16 alpha,17 alpha)-9 alpha-fluoro-11,17,21-trihydroxy-16-methyl pregna [1 alpha,2 beta]-cyclohex 3',4-diene, 3,20-dione], C2 [(11 beta,16 alpha,17 alpha)-9 alpha-fluoro-11,17,21-trihydroxy-16-methyl pregna [1 alpha,2 alpha]-cyclohex 3',4-diene, 3,20-dione], and C3 [(11 beta,17 alpha)-11,17,21-trihydroxy-pregna [1 alpha,2 alpha]-cyclohex 3',4-diene, 3,20-dione] were concluded based on GC-mass and 1H NMR spectroscopic data. The compounds were used to evaluate the effect of introducing extra ring in the structure of the above drugs on their anti-inflammatory behavior. The potencies of the three compounds were compared with that of the mother drugs by the rat hind paw edema test. The results indicate a decrease in C1 potency, expressed as percentage of inflammation inhibition (16.5% versus 24.3% for Dex) or loss of C2 potency (2.0% versus 24.3% for Dex) in dexamethasone adducts. On the other hand, although the prednisolone adduct C3 lost potency too (3.95% versus 26.3% for Pred), but instead it lowered significantly the prednisolone potency on subsequent administration before prednisolone (C3+Pred) (1.30% versus 17.10% for Pred). When prednisolone was administered in equal doses after C3 (10mg/kg), it restored about 60% of its activity. This observation indicates that C3 still retain affinity toward GR without eliciting subsequent events. In other words it has anti prednisolone effect, i.e. anti-glucocorticoid property.