Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues.

Abstract

Abnormal melanogenesis results in excessive production of melanin, leading to pigmentation disorders. As a key and rate-limiting enzyme for melanogenesis, tyrosinase has been considered an important target for developing therapeutic agents of pigment disorders. Despite having an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold, which plays an important role in the potent inhibition of tyrosinase activity, cinnamic acids have not attracted attention as potential tyrosinase inhibitors, due to their low tyrosinase inhibitory activity and relatively high hydrophilicity. Given that cinnamic acids' structure intrinsically features this (E)-scaffold and following our experience that minute changes in the chemical structure can powerfully affect tyrosinase activity, twenty less hydrophilic cinnamamide derivatives were designed as potential tyrosinase inhibitors and synthesised using a Horner-Wadsworth-Emmons reaction. Four of these cinnmamides (4, 9, 14, and 19) exhibited much stronger mushroom tyrosinase inhibition (over 90% inhibition) at 25 µM compared to kojic acid (20.57% inhibition); crucially, all four have a 2,4-dihydroxy group on the β-phenyl ring of the scaffold. A docking simulation using tyrosinase indicated that the four cinnamamides exceeded the binding affinity of kojic acid, and bound more strongly to the active site of tyrosinase. Based on the strength of their tyrosinase inhibition, these four cinnamamides were further evaluated in B16F10 melanoma cells. All four cinnamamides, without cytotoxicity, exhibited higher tyrosinase inhibitory activity (67.33 - 79.67% inhibition) at 25 μM than kojic acid (38.11% inhibition), with the following increasing inhibitory order: morpholino (9) = cyclopentylamino (14) < cyclohexylamino (19) < N-methylpiperazino (4) cinnamamides. Analysis of tyrosinase activity and melanin content in B16F10 cells showed that the four cinnamamides dose-dependently inhibited both cellular tyrosinase activity and melanin content and that their inhibitory activity at 25 μM was much better than that of kojic acid. The results of melanin content analysis well matched those of the cellular tyrosinase activity analysis, indicating that tyrosinase inhibition by the four cinnamamides is a major factor in the reduction of melanin production. These results imply that these four cinnamamides with a 2,4-dihydroxyphenyl group can act as excellent anti-melanogenic agents in the treatment of pigmentation disorders.

• Authors: Sultan Ullah, Chaeun Park, Muhammad Ikram, Dongwan Kang, Sanggwon Lee, Jungho Yang, Yujin Park, Sik Yoon, Pusoon Chun, Hyung Ryong Moon
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 87 Pg. 43-55 (06 2019) ISSN: 1090-2120 [Electronic] United States
• PMID: 30856375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Cinnamates
• Enzyme Inhibitors
• Melanins
• Monophenol Monooxygenase
• cinnamamide

Topics

• Animals
• Cell Survival (drug effects)
• Cinnamates (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Melanins (antagonists & inhibitors, biosynthesis)
• Mice
• Molecular Docking Simulation
• Molecular Structure
• Monophenol Monooxygenase (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Tumor Cells, Cultured