Indole-derived psammaplin A analogues as epigenetic modulators with multiple inhibitory activities
Raquel Pereira1, Rosaria Benedetti, Santiago Pérez-Rodríguez
1Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, Spain.
Journal of Medicinal Chemistry
|October 4, 2012
Summary
Researchers modified psammaplin A using an indole ring, creating potent epigenetic inhibitors. These novel indole psammaplin A analogues show enhanced activity and multi-target inhibition, offering new therapeutic potential for epigenetic disorders.
Area of Science:
- Medicinal Chemistry
- Epigenetics
- Pharmacology
Background:
- Psammaplin A is a natural product with dual HDAC and DNMT inhibitory activity.
- Epigenetic dysregulation is implicated in various disorders.
- Novel epigenetic modulators are needed.
Purpose of the Study:
- To synthesize and characterize indole-based psammaplin A analogues.
- To evaluate their epigenetic inhibitory activities.
- To explore structure-activity relationships (SAR) for improved potency and multi-target engagement.
Main Methods:
- Synthesis of indole psammaplin A analogues via a multi-step sequence.
- Biochemical assays to assess HDAC, DNMT, and SIRT inhibitory activity.
- Cellular assays using U937 and MCF-7 cell lines.
Main Results:
- A series of indole psammaplin A analogues were successfully synthesized.
- Many analogues exhibited enhanced potency compared to the parent compound.
- Compound 4a (UVI5008) demonstrated dual HDAC/DNMT inhibition and SIRT inhibition.
Conclusions:
- Indole modification of psammaplin A yields potent multi-target epigenetic inhibitors.
- SAR insights guide optimization for pharmacological profiles.
- These derivatives are promising candidates for modulating epigenetic disorders.
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