Nouveaux hémiindigoïdes sélectifs ciblant la tyrosinase humaine : détection et suppression de la mélanogenèse

Skin is the first defense system against environmental aggressions. Precisely, melanins are skin pigments involved in the protection against UV radiations and free radicals. However, their overexpression leads to both skin disorders and melanoma multiresistance issues against all traditional anti-cancer therapies.Inhibiting the human tyrosinase enzyme (hsTY) constitutes the simplest and most classical strategy to reduce the production of melanin, but the state of the art regarding dedicated inhibitors of isolated hsTY is only at its beginning. Therefore, in this work we investigate the effect of aurone derivatives on human tyrosinase, starting from a parent compound : 2-hydroxypyridine-N-oxide embedded 6-hydroxyaurone (aurone - HOPNO) previously identified (Ki = 0.35 µM) that suffered from solubility and cell penetration issues. The identification of 4-butylresorcinol and thiamidol as powerful hsTY inhibitors inspired us for the development of a series of compounds with a resorcinol moiety B ring which is expected to chelate the dicopper center at the active site. Modifications on C and A rings were made concomitantly to reach specific hsTY residues located further from the coppers, ensuring high selectivity profiles. The synthesized hemiindigoid compounds were assessed to evaluate their ability to inhibit melanin production from melanoma cells MNT-1. So far, it seems that polyphenolic substitutions on the A ring promotes interactions with key residues, thus improving activities. Overall, the study endorses the use of the hemiindigoid scaffolds for the development of new potent and selective inhibitors of tyrosinase.La peau est la première barrière de défense contre les agressions environnementales. En effet, la mélanine, un pigment cutané, est responsable de cette protection contre les rayons UV et les radicaux libres. Cependant, sa surexpression entraîne à la fois des troubles cutanés et des problèmes de multirésistance du mélanome contre toutes les thérapies anticancéreuses traditionnelles.L'inhibition de la tyrosinase humaine (hsTY) constitue la stratégie la plus simple et la plus classique pour réduire la production de mélanine, mais l’état de l’art concernant le développement d’inhibiteurs de hsTY n'en est qu'à ses débuts. Par conséquent, dans cette étude, nous étudions l'effet de dérivés aurones sur la tyrosinase humaine, à partir d'un composé parent : le 2-hydroxypyridine-N-oxide-6-hydroxyaurone (aurone - HOPNO) précédemment identifié (Ki = 0,35 µM) qui souffre cependant de problèmes de solubilité et de pénétration cellulaire. L'identification du 4-butylrésorcinol et du thiamidol en tant qu'inhibiteurs puissants de hsTY nous a inspiré pour le développement d'une série de composés avec un groupement résorcinol (sur le cycle B), capable de chélater le centre à cuivre du site actif. Des modifications sur les cycles C et B ont été effectuées simultanément pour interagir avec des résidus hsTY spécifiques éloignés du centre à cuivre, assurant une sélectivité élevée. Les composés synthétisés ont été évalués pour déterminer leur capacité à inhiber la production de mélanine à partir de cellules de mélanome MNT-1. Jusqu'à présent, il semble que les substitutions polyphénoliques sur le cycle A favorisent les interactions avec des résidus clés, améliorant ainsi l’activité. Dans l'ensemble, cette étude montre l'intérêt de l’utilisation de squelettes de type hémiindigoïde pour le développement de nouveaux inhibiteurs plus actifs et sélectifs de la tyrosinase

New selective hemiindigoids targeting human tyrosinase : detection and suppression of melanogenesis

La peau est la première barrière de défense contre les agressions environnementales. En effet, la mélanine, un pigment cutané, est responsable de cette protection contre les rayons UV et les radicaux libres. Cependant, sa surexpression entraîne à la fois des troubles cutanés et des problèmes de multirésistance du mélanome contre toutes les thérapies anticancéreuses traditionnelles.L'inhibition de la tyrosinase humaine (hsTY) constitue la stratégie la plus simple et la plus classique pour réduire la production de mélanine, mais l’état de l’art concernant le développement d’inhibiteurs de hsTY n'en est qu'à ses débuts. Par conséquent, dans cette étude, nous étudions l'effet de dérivés aurones sur la tyrosinase humaine, à partir d'un composé parent : le 2-hydroxypyridine-N-oxide-6-hydroxyaurone (aurone - HOPNO) précédemment identifié (Ki = 0,35 µM) qui souffre cependant de problèmes de solubilité et de pénétration cellulaire. L'identification du 4-butylrésorcinol et du thiamidol en tant qu'inhibiteurs puissants de hsTY nous a inspiré pour le développement d'une série de composés avec un groupement résorcinol (sur le cycle B), capable de chélater le centre à cuivre du site actif. Des modifications sur les cycles C et B ont été effectuées simultanément pour interagir avec des résidus hsTY spécifiques éloignés du centre à cuivre, assurant une sélectivité élevée. Les composés synthétisés ont été évalués pour déterminer leur capacité à inhiber la production de mélanine à partir de cellules de mélanome MNT-1. Jusqu'à présent, il semble que les substitutions polyphénoliques sur le cycle A favorisent les interactions avec des résidus clés, améliorant ainsi l’activité. Dans l'ensemble, cette étude montre l'intérêt de l’utilisation de squelettes de type hémiindigoïde pour le développement de nouveaux inhibiteurs plus actifs et sélectifs de la tyrosinase.Skin is the first defense system against environmental aggressions. Precisely, melanins are skin pigments involved in the protection against UV radiations and free radicals. However, their overexpression leads to both skin disorders and melanoma multiresistance issues against all traditional anti-cancer therapies.Inhibiting the human tyrosinase enzyme (hsTY) constitutes the simplest and most classical strategy to reduce the production of melanin, but the state of the art regarding dedicated inhibitors of isolated hsTY is only at its beginning. Therefore, in this work we investigate the effect of aurone derivatives on human tyrosinase, starting from a parent compound : 2-hydroxypyridine-N-oxide embedded 6-hydroxyaurone (aurone - HOPNO) previously identified (Ki = 0.35 µM) that suffered from solubility and cell penetration issues. The identification of 4-butylresorcinol and thiamidol as powerful hsTY inhibitors inspired us for the development of a series of compounds with a resorcinol moiety B ring which is expected to chelate the dicopper center at the active site. Modifications on C and A rings were made concomitantly to reach specific hsTY residues located further from the coppers, ensuring high selectivity profiles. The synthesized hemiindigoid compounds were assessed to evaluate their ability to inhibit melanin production from melanoma cells MNT-1. So far, it seems that polyphenolic substitutions on the A ring promotes interactions with key residues, thus improving activities. Overall, the study endorses the use of the hemiindigoid scaffolds for the development of new potent and selective inhibitors of tyrosinase

Nouveaux hémiindigoïdes sélectifs ciblant la tyrosinase humaine : détection et suppression de la mélanogenèse

Skin is the first defense system against environmental aggressions. Precisely, melanins are skin pigments involved in the protection against UV radiations and free radicals. However, their overexpression leads to both skin disorders and melanoma multiresistance issues against all traditional anti-cancer therapies.Inhibiting the human tyrosinase enzyme (hsTY) constitutes the simplest and most classical strategy to reduce the production of melanin, but the state of the art regarding dedicated inhibitors of isolated hsTY is only at its beginning. Therefore, in this work we investigate the effect of aurone derivatives on human tyrosinase, starting from a parent compound : 2-hydroxypyridine-N-oxide embedded 6-hydroxyaurone (aurone - HOPNO) previously identified (Ki = 0.35 µM) that suffered from solubility and cell penetration issues. The identification of 4-butylresorcinol and thiamidol as powerful hsTY inhibitors inspired us for the development of a series of compounds with a resorcinol moiety B ring which is expected to chelate the dicopper center at the active site. Modifications on C and A rings were made concomitantly to reach specific hsTY residues located further from the coppers, ensuring high selectivity profiles. The synthesized hemiindigoid compounds were assessed to evaluate their ability to inhibit melanin production from melanoma cells MNT-1. So far, it seems that polyphenolic substitutions on the A ring promotes interactions with key residues, thus improving activities. Overall, the study endorses the use of the hemiindigoid scaffolds for the development of new potent and selective inhibitors of tyrosinase.La peau est la première barrière de défense contre les agressions environnementales. En effet, la mélanine, un pigment cutané, est responsable de cette protection contre les rayons UV et les radicaux libres. Cependant, sa surexpression entraîne à la fois des troubles cutanés et des problèmes de multirésistance du mélanome contre toutes les thérapies anticancéreuses traditionnelles.L'inhibition de la tyrosinase humaine (hsTY) constitue la stratégie la plus simple et la plus classique pour réduire la production de mélanine, mais l’état de l’art concernant le développement d’inhibiteurs de hsTY n'en est qu'à ses débuts. Par conséquent, dans cette étude, nous étudions l'effet de dérivés aurones sur la tyrosinase humaine, à partir d'un composé parent : le 2-hydroxypyridine-N-oxide-6-hydroxyaurone (aurone - HOPNO) précédemment identifié (Ki = 0,35 µM) qui souffre cependant de problèmes de solubilité et de pénétration cellulaire. L'identification du 4-butylrésorcinol et du thiamidol en tant qu'inhibiteurs puissants de hsTY nous a inspiré pour le développement d'une série de composés avec un groupement résorcinol (sur le cycle B), capable de chélater le centre à cuivre du site actif. Des modifications sur les cycles C et B ont été effectuées simultanément pour interagir avec des résidus hsTY spécifiques éloignés du centre à cuivre, assurant une sélectivité élevée. Les composés synthétisés ont été évalués pour déterminer leur capacité à inhiber la production de mélanine à partir de cellules de mélanome MNT-1. Jusqu'à présent, il semble que les substitutions polyphénoliques sur le cycle A favorisent les interactions avec des résidus clés, améliorant ainsi l’activité. Dans l'ensemble, cette étude montre l'intérêt de l’utilisation de squelettes de type hémiindigoïde pour le développement de nouveaux inhibiteurs plus actifs et sélectifs de la tyrosinase

Design and synthesis of 4-amino-2’,4’-dihydroxyindanone derivatives as potent inhibitors of tyrosinase and melanin biosynthesis in human melanoma cells

Melanogenesis inhibition constitutes a privileged therapeutic solution to treat skin hyperpigmentation, a major dermatological concern associated with the overproduction of melanin by human tyrosinase (hsTYR). Despite the existence of many well-known TYR (tyrosinase) inhibitors commercialized in skin formulations, their hsTYR-inhibition efficacy remains poor since most of them were investigated over mushroom tyrosinase (abTYR), a model with low homology relative to hsTYR. Considering the need for new potent hsTYR inhibitors, we designed and synthesized a series of indanones starting from 4-hydroxy compound 1a, one of the two most active derivatives reported to date against the human enzyme, together with marketed thiamidol. We observed that analogues featuring 4-amino and 4-amido-2’,4’-dihydroxyindanone motifs showed two- to ten-fold increase in activity over human melanoma MNT-1 cell lysates, and a ten-fold improvement in a 4-days whole-cell experiment, compared to parent analogue 1a. Molecular docking investigation was performed for the most promising 4-amido derivatives and suggested a plausible interaction pattern with the second coordination sphere of hsTYR, notably through hydrogen bonding with Glu203, confirming their impact in the binding mode with hsTYR active site

Resorcinol-based hemiindigoid derivatives as human tyrosinase inhibitors and melanogenesis suppressors in human melanoma cells

International audienceHuman tyrosinase (hsTYR) catalyzes the key steps of melanogenesis, making it a privileged target for reducing melanin production in vivo. However, very few hsTYR inhibitors have been reported so far in the literature, whereas thousands of mushroom tyrosinase (abTYR) inhibitors are known. Yet, as these enzymes are actually very different, including at their active sites, there is an urgent need for new true hsTYR inhibitors in order to enable human-directed pharmacological and dermocosmetic applications without encountering the inefficiency and toxicity issues currently triggered by kojic acid or hydroquinone. Starting from the two most active compounds reported to date, i.e. a 2-hydroxypyridine-embedded aurone and thiamidol, we combined herein key structural elements and developed new nanomolar hsTYR inhibitors with cell-based activity. From a complete series of thirty-eight synthesized derivatives, excellent inhibition values were obtained for two compounds in both human melanoma cell lysates and purified hsTYR assays, and a promising improvement was observed in whole cell experiments

Resorcinol-based hemiindigoid derivatives as human tyrosinase inhibitors and melanogenesis suppressors in human melanoma cells

Human tyrosinase (hsTYR) catalyzes the key steps of melanogenesis, making it a privileged target for reducing melanin production in vivo. However, very few hsTYR inhibitors have been reported so far in the literature, whereas thousands of mushroom tyrosinase (abTYR) inhibitors are known. Yet, as these enzymes are actually very different, including at their active sites, there is an urgent need for new true hsTYR inhibitors in order to enable human-directed pharmacological and dermocosmetic applications without encountering the inefficiency and toxicity issues currently triggered by kojic acid or hydroquinone. Starting from the two most active compounds reported to date, i.e. a 2-hydroxypyridine-embedded aurone and thiamidol, we combined herein key structural elements and developed new nanomolar hsTYR inhibitors with cell-based activity. From a complete series of thirty-eight synthesized derivatives, excellent inhibition values were obtained for two compounds in both human melanoma cell lysates and purified hsTYR assays, and a promising improvement was observed in whole cell experiments

Aurones and derivatives as promising New Delhi metallo-β-lactamase (NDM-1) inhibitors

International audienceBacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-β-lactamases (MBLs) able to hydrolytically inactivate β-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-β-lactamase-1 (NDM-1) is still considered as one of the most relevant targets for inhibitor development. Following a fragment-based strategy to find new NDM-1 inhibitors, we identified aurone as a promising scaffold. A series of 60 derivatives were then evaluated and two of them were identified as promising inhibitors with Ki values as low as 1.7 and 2.5 µM. Moreover, these two most active compounds were able to potentiate meropenem in in vitro antimicrobial susceptibility assays. The molecular modelling provided insights about their likely interactions with the active site of NDM-1, thus enabling further improvement in the structure of this new inhibitor family

Aurone derivatives as promising antibacterial agents against resistant Gram-positive pathogens

International audienceA set of variously substituted aurones was synthesized and evaluated against Methicillin-Resistant S. aureus (MRSA) and P. aeruginosa. Several analogues were found active against MRSA, but no effect was recorded against P. aeruginosa. Compounds 27, 30 and 33 showed low cytotoxicity, and were tested against a full range of bacterial (Gram-positive and Gram-negative) and fungal species, including resistant strains. These aurones displayed a selective inhibition of Gram-positive bacteria with excellent Therapeutic Index values, while showing no significant action on several Gram-negative strains, H. pylori and V. alginolyticus being the only susceptible strains among the Gram-negative bacteria tested. A per-meabilization assay showed that the antibacterial activity of at least some of the aurones could be linked to alterations of the bacterial membrane. Overall, this study endorses the use of the aurone scaffold for the development of new potent and selective antibacterial agents