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.

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.

Advances in the Design of Genuine Human Tyrosinase Inhibitors for Targeting Melanogenesis and Related Pigmentations.

Human tyrosinase (hsTYR) is the key enzyme ensuring the conversion of l-tyrosine to dopaquinone, thereby initiating melanin synthesis, i.e., melanogenesis. Although the protein has long been familiar, knowledge about its three-dimensional structure and efficient overexpression protocols emerged only recently. Consequently, for decades medicinal chemistry studies aiming at developing skin depigmenting agents relied almost exclusively on biological assays performed using mushroom tyrosinase (abTYR), producing a plethoric literature, often of little useful purpose. Indeed, several recent reports have pointed out spectacular differences in terms of interaction patterns and inhibition values between hsTYR and abTYR, including for widely used standard tyrosinase inhibitors. In this review, we summarize the last developments regarding the potential role of hsTYR in human pathologies, the advances in recombinant expression systems and structural data retrieving, and the pioneer generation of true hsTYR inhibitors. Finally, we present suggestions for the design of future inhibitors of this highly attractive target in pharmacology and dermocosmetics.