- Diclofenac-derived hybrids for treatment of actinic keratosis and squamous cell carcinoma
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In this work, hybrid compounds 1-4 obtained by conjugation of the non-steroidal anti-inflammatory drug diclofenac, with natural molecules endowed with antioxidant and antiproliferative activity were prepared. The antiproliferative activity of these hybrids was evaluated on immortalized human keratinocyte (HaCaT) cells stimulated with epidermal growth factor (EGF), an actinic keratosis (AK) model, and on human squamous cell carcinoma (SCC) cells (A431). Hybrid 1 presented the best activity in both cell models. Self-assembling surfactant nanomicelles have been chosen as the carrier to drive the hybrid 1 into the skin; the in vitro permeation through and penetration into pig ear skin have been evaluated. Among the nanostructured formulations tested, Nano3Hybrid20 showed a higher tendency of the hybrid 1 to be retained in the skin rather than permeating it, with a desirable topical and non-systemic action. On these bases, hybrid 1 may represent an attractive lead scaffold for the development of new treatments for AK and SCC.
- Tampucci, Silvia,Carpi, Sara,Digiacomo, Maria,Polini, Beatrice,Fogli, Stefano,Burgalassi, Susi,MacChia, Marco,Nieri, Paola,Manera, Clementina,Monti, Daniela
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- Specificity of esterases and structure of prodrug esters: Reactivity of various acylated acetaminophen compounds and acetylaminobenzoated compounds
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The relative rates of enzymatically catalyzed hydrolysis of various esters of p-acetylaminobenzoic acid (APAB) and variously acylated acetaminophen (APAP) derivatives were measured. Neutral, anionic, and cationic esters were examined. The enzyme sources adopted were rat intestinal homogenate, rat liver homogenate, rat plasma, and a partly purified commercial enzyme. In both APAB and APAP esters, neutral esters were the most sensitive of the enzyme sources examined, and the sensitivity was due to the carbon chain length. The APAP esters were enzymatically more stable than the APAP esters. The relative rates of hydrolysis of these esters varied depending on the enzyme source. The ability of structure recognition was good in rat intestinal homogenate, but weak in rat plasma. These results suggest that ester prodrugs can be designed to cleave preferentially at selected sites along the pathway between absorption and disposition in the body.
- Seki,Kawaguchi,Higuchi
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p. 855 - 860
(2007/10/02)
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