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Updated: Oct 8, 2025
Quantification of Hypopigmentation Activity In Vitro
Published on: March 6, 2019
Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new anti-vitiligo
Bi-Juan Yang1, Shi-Rui Fan2, Xin-Fang Zhang3
1State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650031, Yunnan, China.
Abstract:
Humans have been suffering from vitiligo for a long time. Target vitiligo drugs have yet been approved. Activation of Wnt/β-catenin signalling has potential in the therapeutic use of vitiligo, so exploring new drugs that specifically directly activate Wnt is worthwhile to obtain new anti-vitiligo agents. In this work, two portions design and synthesis were put into effect. firstly, 17 phenanthridine derivatives with C-4 substitutes were designed and synthesized, which compounds 4, 6, 12, 13 served as H-acceptor with protein showed enhance melanogenesis activity; Secondly, 7 hybrid new scaffolds of compounds were designed and synthesized, scaffold hopping compound 36 that aromatic benzene was replaced pyrazole on ring C showed enhance melanogenesis and tyrosinase activity; The last and most important, a comprehensive optimization and SARs of compound 36 were carried out, compounds 41 and 43 shared phenolic hydroxyl or 3-methyl-pyridine substitutes at C-7 position remarkably improved the capacity of melanogenesis and tyrosinase activity. Compound 43 were identified as new anti-vitiligo agents that specifically activate the Wnt/β-catenin signalling pathway by targeting Axin. Structure-activity relationship analysis implied that H-acceptor substitutions at the C-4 position and phenolic hydroxyl or pyridine substitutions at the C-7 position would improve the activities of the compounds. These findings reveal a new therapeutic strategy for vitiligo, and compounds 41 and 43 may represent potential compounds for vitiligo treatment.
Insights
New research explores Wnt/β-catenin pathway activators for vitiligo treatment. Compound 43, targeting Axin, shows promise as a novel anti-vitiligo agent by enhancing melanogenesis and tyrosinase activity.
Area of Science:
- Dermatology and Pharmacology
- Medicinal Chemistry
- Molecular Biology
Background:
- Vitiligo is a chronic skin condition with no targeted therapies.
- The Wnt/β-catenin signaling pathway is a promising target for vitiligo treatment.
- Developing novel drugs that activate Wnt signaling is crucial for new anti-vitiligo agents.
Purpose of the Study:
- To design and synthesize novel phenanthridine derivatives and hybrid scaffolds as potential anti-vitiligo agents.
- To identify compounds that activate the Wnt/β-catenin signaling pathway.
- To optimize lead compounds and explore structure-activity relationships (SARs) for enhanced melanogenesis and tyrosinase activity.
Main Methods:
- Synthesis of 17 phenanthridine derivatives with C-4 substituents.
- Design and synthesis of 7 hybrid new scaffolds, including scaffold hopping.
- Comprehensive optimization and SAR analysis of lead compounds, focusing on C-7 substitutions.
Main Results:
- Phenanthridine derivatives (compounds 4, 6, 12, 13) with H-acceptor substitutions at C-4 enhanced melanogenesis.
- Scaffold hopping compound 36, with a pyrazole replacing benzene on ring C, showed enhanced melanogenesis and tyrosinase activity.
- Optimized compounds 41 and 43, with C-7 phenolic hydroxyl or pyridine substitutions, significantly improved melanogenesis and tyrosinase activity. Compound 43 specifically activates Wnt/β-catenin by targeting Axin.
Conclusions:
- Compound 43 is identified as a potential new anti-vitiligo agent targeting the Wnt/β-catenin pathway.
- Specific substitutions at C-4 (H-acceptor) and C-7 (phenolic hydroxyl or pyridine) are key for improving compound activity.
- Compounds 41 and 43 represent promising candidates for future vitiligo therapeutic development.
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