Screening for tyrosinase inhibitors from actinomycetes; identification of trichostatin derivatives from Streptomyces sp. CA-129531 and scale up production in bioreactor. Issue 6 (15th March 2020)

• Record Type: Journal Article
• Authors: Georgousaki, Katerina; Tsafantakis, Nikolaos; Gumeni, Sentiljana; Gonzalez, Ignacio; Mackenzie, Thomas Andrew; Reyes, Fernando; Lambert, Carole; Trougakos, Ioannis P.; Genilloud, Olga; Fokialakis, Nikolas
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 6(2020)
• Publication Date: 2020-03-15
• Subjects: Tyrosinase inhibitors -- Trichostatin derivatives -- Secondary metabolites, Streptomyces sp. -- Bioreactor -- Enzyme kinetics studies; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.126952
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: In the course of a primary screening of 614 microbial actinomycete extracts for the discovery of tyrosinase inhibitors, the EtOAc extract of the fermentation broth of the strain Streptomyces sp. CA-129531 isolated from a Martinique sample, exhibited in cell free and cell-based assays the most promising activity (IC50 value of 63 μg/mL). Scaled-up production in a bioreactor led to the isolation of one new trichostatic acid analogue, namely trichostatic acid B (1 ), along with six known trichostatin derivatives (2 –7 ), four diketopiperazines (8 –11 ), two butyrolactones (12 –13 ) and one hydroxamic acid siderophore (14 ). Among them, trichostatin A (4 ) showed a Ki value of 6.1 μM and six times stronger anti-tyrosinase activity (IC50 2.18 μΜ) than kojic acid (IC50 14.07 μΜ) used as a positive control. Deoxytrichostatin A (6 ) displayed also strong inhibitory activity against tyrosinase (IC50 19.18 μΜ). Trichostatin A production in bioreactor started together with the exponential phase of growth (day 4) and the maximum concentration was reached at day 9 (2.67 ± 0.13 μg/mL). Despite the cytotoxicity of some individual components, the EtOAc extract showed no cytotoxic effect on HepG2, A2058, A549, MCF-7 and MIA PaCa-2 cell lines, (IC50 >2.84 mg/mL) and against BG fibroblasts at the concentrations where the whitening effect was exerted, reassuring its safety and great tyrosinase inhibitory potential.