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                <term xml:lang="en">Cell culture</term>
                <term xml:lang="en">chemical analysis</term>
                <term xml:lang="en">skin physiology</term>
                <term xml:lang="en">2-5-diketopiperazines</term>
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                <term xml:lang="en">AGEs/CML clearance</term>
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              <p>Objective: Glycation is a common non‐enzymatic reaction between proteins and sugars, resulting in the formation of advanced glycation end products (AGEs) in the human body. As can be seen in diabetic patients, the accumulation of AGEs in the skin has aesthetic consequences (wrinkles, brown spots and yellowish complexion). Therefore, the objective of this work was to find compounds isolated from natural sources that could eliminate the final AGEs accumulated in the skin with ageing.Methods and results: A preliminary screening performed on a bank of microbial extracts and pure compounds showed that 2,5‐Diketopiperazines (DKPs), as well as the extract of Sphingobacterium sp (SNB‐CN13), reduced the presence of AGEs in fibroblasts by −28% and −23%, respectively. In this article, we present the dereplication approach used to reveal the presence of 26 different DKPs in the crude extract of Sphingobacterium sp. Bioguided fractionation has led to the isolation of 12 of them, whose identity has been confirmed by HRMS and NMR. A green synthesis approach has been developed to synthesize 3 symmetrical DKPs. The biological activity of all DKPs was evaluated by the development of an in vitro test using immunocytochemistry to reveal the presence of AGE carboxymethyl‐lysine in human dermal fibroblasts.Conclusion: Our work shows for the first time that DKPs decrease the amount of carboxymethyl‐lysine AGE in elderly human dermal fibroblasts grown in vitro. Therefore, diketopiperazines can be considered as compounds of interest for dermatological and cosmetic applications with an anti‐ageing aim.</p>
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