Efficacy, Stability, and Safety Evaluation of New Polyphenolic Xanthones Towards Identification of Bioactive Compounds to Fight Skin Photoaging

Antioxidants have long been used in the cosmetic industry to prevent skin photoaging, which is mediated by oxidative stress, making the search for new antioxidant compounds highly desirable in this field. Naturally occurring xanthones are polyphenolic compounds that can be found in microorganisms, fungi, lichens, and some higher plants. This class of polyphenols has a privileged scaffold that grants them several biological activities. We have previously identified simple oxygenated xanthones as promising antioxidants and disclosed as hit, 1,2-dihydroxyxanthone (1). Herein, we synthesized and studied the potential of xanthones with different polyoxygenated patterns as skin antiphotoaging ingredients. In the DPPH antioxidant assay, two newly synthesized derivatives showed IC₅₀ values in the same range as ascorbic acid. The synthesized xanthones were discovered to be excellent tyrosinase inhibitors and weak to moderate collagenase and elastase inhibitors but no activity was revealed against hyaluronidase. Their metal-chelating effect (FeCl₃ and CuCl₂) as well as their stability at different pH values were characterized to understand their potential to be used as future cosmetic active agents. Among the synthesized polyoxygenated xanthones, 1,2-dihydroxyxanthone (1) was reinforced as the most promising, exhibiting a dual ability to protect the skin against UV damage by combining antioxidant/metal-chelating properties with UV-filter capacity and revealed to be more stable in the pH range that is close to the pH of the skin. Lastly, the phototoxicity of 1,2-dihydroxyxanthone (1) was evaluated in a human keratinocyte cell line and no phototoxicity was observed in the concentration range tested.This research was supported by national funds through FCT, Foundation for Science and Technology, within the scope of UIDB/04423/2020 and UIDP/04423/2020 under the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), cofinanced by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds, as well as CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019, and supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019). Thanks are also due to FCT, the European Union, QREN, FEDER, COMPETE, by funding cE3c center (Ref. UID/BIA/00329/2019) and Direcao Regional da Ciencia e Tecnologia (Azores Government) by funding Azorean Biodiversity Group.info:eu-repo/semantics/publishedVersio

New heterocyclic polyphenols with skin anti-aging potential

Xanthones or dibenzo-gamma-pyrones are heterocyclic polyphenolic compounds that can be found in microorganisms, fungi, lichens, and some higher plants. Structure-activity relationship studies emerged from a library of natural and synthetic polyoxygenated have suggested that xanthones with vicinal diol groups have promising antioxidant activity. Antioxidants have long been used in the cosmetic industry to prevent or minimize skin aging which is mediated by oxidative stress, making the search for new antioxidant agents highly desirable in this field. Considering the structure-activity relationship studies, it was hypothesized that trioxygenated xanthones could be promising antioxidants with potential as skin anti-aging ingredients. Hence, the synthesis of trioxygenated xanthones was attempted by the Smiles rearrangement pathway and also via acyl radical cyclization. The Smiles rearrangement pathway failed to yield the ester intermediate that was essential in this approach and was therefore abandoned. In the acyl radical cyclization method it was possible to obtain the 1,4-dihydroxy-3-methoxy-9H-xanthen-9-one. The antioxidant activity of this new xanthone as well as of four other polyoxygenated xanthones was evaluated by the DPPH assay, and two new derivatives showed IC50 values in the same range as the ascorbic acid. Almost all of the compounds were excellent tyrosinase inhibitors, more active than control inhibitor kojic acid. Concerning the other skin-degrading enzymes, the compounds tested were weak to moderate collagenase inhibitors, and showed no activity against elastase. The stability in presence of metal ions (FeCl3 and CuCl2) and dependence of the pH of their aqueous solutions was also studied, as well as their solubility in water and glycerol. Finally, the phototoxicity of the most promising xanthone was evaluated in a human keratinocyte cell line and no phototoxicity was observed in the concentration range tested, which is an important requirement for topical ingredients. Acknowledgements: This work was developed under the Strategic Funding UID/Multi/04423/2019 and Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds, QREN,FEDER, COMPETE, by funding the cE3c centre (Ref. UID/BIA/00329/2019) and Azores DRCT for funding ABG. This work was also supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019

Xanthones for melanogenesis inhibition : Molecular docking and QSAR studies to understand their anti-tyrosinase activity

The human skin is constantly exposed to external factors that affect its integrity, UV radiation being one of the main stress factors. The repeated exposure to this radiation leads to increased production of Reactive Oxygen Species (ROS) which activate a series of processes involved in photoaging. Excessive UV exposure also exacerbates melanin production leading to a variety of pigmentation disorders. Xanthones are reported to exhibit properties that prevent deleterious effects of UV exposure and high levels of ROS in the organism, so in this work a wide library of xanthones with different patterns of substitution was synthesized and tested for their inhibitory activity against the skin enzymes tyrosinase, elastase, collagenase and hyaluronidase, many of which were evaluated for the first time. Most of the compounds were tyrosinase inhibitors, with the best one (xanthone 27) presenting an IC50 of 1.9 µM, which is approximately 6 times lower than the IC50 of the positive control kojic acid. Concerning the other enzymes, only one compound presented IC50 lower than 150 µM in elastase inhibition (xanthone 14 = 91.8 µM) and none in collagenase and hyaluronidase inhibition. A QSAR model for tyrosinase inhibitory activity was built using six molecular descriptors, with a partial negative surface area descriptor and the relative number of oxygen atoms being positively contributing to the tyrosinase inhibitory activity. Docking using AutoDock Vina shows that all the tested compounds have more affinity to mushroom tyrosinase than kojic acid. Docking results implied that the tyrosinase inhibitory mechanisms of xanthonic derivatives are attributed to an allosteric interaction. Taken together, these data suggest that xanthones might be useful scaffolds for the development of new and promising candidates for the treatment of pigmentation-related disorders and for skin whitening cosmetic products.This research was supported by national funds through FCT, Foundation for Science and Technology, within the scope of UIDB/04423/2020 and UIDP/04423/2020 under the project PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), cofinanced by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds, and supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019). Thanks are also due to FCT, the European Union, QREN, FEDER, COMPETE, by funding cE3c center (Ref. UID/BIA/00329/2019) and Direção Regional da Ciência e Tecnologia (Azores Government) by funding Azorean Biodiversity Group.info:eu-repo/semantics/publishedVersio