Abstract
In this study the solvolysis of newly synthesized fluocinolone acetonide C-21 esters was analysed in comparison with fluocinonide during a 24-hour period of time. The solvolysis was performed in an ethanol-water (90:10 v/v) mixture using the excess of NaHCO3. The solvolytic mixtures of each investigated ester have been assayed by a RP-HPLC method using isocratic elution with methanol-water (75:25 v/v); flow rate 1 mL/min; detection at 238 nm; temperature 25 °C. Solvolytic rate constants were calculated from the obtained data. Geometry optimizations and charges calculations were carried out by Gaussian W03 software. A good correlation (R = 0.9924) was obtained between solvolytic rate constants and the polarity of the C-O2 bond of those esters. The established relation between solvolytic rate constant (K) and lipophilicity (cLogP) with experimental anti-inflammatory activity could be indicative for topical corticosteroid prodrug activation.
Highlights
Corticosteroids are used topically for their anti-inflammatory and immunosuppressive actions.Applied in this fashion, to large areas, when the skin is injured, or under occlusive dressings, corticosteroids may be absorbed in sufficient amounts to cause systemic effects [1].the therapy with corticosteroids is limited both by systemic and local side effects
In order to increase benefit/risk ratio [2] the series of novel α-alkoxyalkanoyl and α-aryloxyalkanoyl esters with higher lipophilicity have been synthesized in our laboratory as analogues of fluocinolone acetonide 21-acetate [3]
The general pathway of fluocinolone acetonide C-21 ester solvolysis is shown in Scheme 1
Summary
Corticosteroids are used topically for their anti-inflammatory and immunosuppressive actions.Applied in this fashion, to large areas, when the skin is injured, or under occlusive dressings, corticosteroids may be absorbed in sufficient amounts to cause systemic effects [1].the therapy with corticosteroids is limited both by systemic and local side effects. Corticosteroids are used topically for their anti-inflammatory and immunosuppressive actions. Applied in this fashion, to large areas, when the skin is injured, or under occlusive dressings, corticosteroids may be absorbed in sufficient amounts to cause systemic effects [1]. In order to increase benefit/risk ratio [2] the series of novel α-alkoxyalkanoyl and α-aryloxyalkanoyl esters with higher lipophilicity have been synthesized in our laboratory as analogues of fluocinolone acetonide 21-acetate (fluocinonide) [3]. Fluocinolone acetonide 21-acetate (FA-21-Ac) is about five times more potent than its active form fluocinolone acetonide (FA) due to enhanced lipophilicity and percutaneous absorption [4,5]. The new synthesized corticosteroid esters: fluocinolone acetonide
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