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Tyrosinase, an important oxidase involved in the primary immune response in humans, can sometimes become problematic as it can catalyze undesirable oxidation reactions. Therefore, for decades there has been a strong pharmaceutical interest in the discovery of novel inhibitors of this enzyme. Recent studies have also indicated that tyrosinase inhibitors can potentially be used in the treatment of melanoma cancer. Over the years, many new tyrosinase inhibitors have been discovered from various natural sources; however, marine natural products (MNPs) have contributed only a small number of promising candidates. Therefore, in this study we focused on the discovery of new MNP tyrosinase inhibitors of marine cyanobacterial and algal origins. A colorimetric tyrosinase inhibitory assay was used to screen over 4,500 marine extracts against mushroom tyrosinase ( A. bisporus ). Our results revealed that scytonemin monomer (ScyM), a pure compound from our compound library and also the monomeric last-step precursor in the biosynthesis of the well-known cyanobacterial sunscreen pigment “scytonemin,” consistently showed the highest tyrosinase inhibitory score. Determination of the half maximal inhibitory concentration (IC 50 ) further indicated that ScyM is more potent than the commonly used commercial inhibitor standard “kojic acid” (KA; IC 50 of ScyM: 4.90 μM vs. IC 50 of KA: 11.31 μM). After a scaled-up chemical synthesis of ScyM as well as its O -methyl analog (ScyM-OMe), we conducted a series of follow-up studies on their structures, inhibitory properties, and mode of inhibition. Our results supported ScyM as the second case ever of a novel tyrosinase inhibitory compound based on a marine cyanobacterial natural product. The excellent in vitro performance of ScyM makes it a promising candidate for applications such as a skin-whitening agent or an adjuvant therapy for melanoma cancer treatment.
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Derivatives of the Fungal Natural Product Illudalic Acid Inhibit the Activity of Protein Histidine Phosphatase PHPT1
Abstract PHPT1 is a protein histidine phosphatase that has been implicated in several disease pathways, but the chemical tools necessary to study the biological roles of this enzyme and investigate its utility as a therapeutic target have yet to be developed. To this end, the discovery of PHPT1 inhibitors is an area of significant interest. Here, we report an investigation of illudalic acid and illudalic acid analog‐based inhibition of PHPT1 activity. Four of the seven analogs investigated had IC50values below 5 μM, with the most potent compound (IA1‐8H2) exhibiting an IC50value of 3.4±0.7 μM. Interestingly, these compounds appear to be non‐covalent, non‐competitive inhibitors of PHPT1 activity, in contrast to other recently reported PHPT1 inhibitors. Mutating the three cysteine residues to alanine has no effect on inhibition, indicating that cysteine is not critical for interactions between inhibitor and enzyme.
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- Award ID(s):
- 2003513
- PAR ID:
- 10423114
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemMedChem
- Volume:
- 18
- Issue:
- 15
- ISSN:
- 1860-7179
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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