Development of new HO-1 inhibitors by a thorough scaffold-hopping analysis
Giuseppe Floresta1, Valeria Pittalà2, Valeria Sorrenti2
1Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy; Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy.
Abstract:
HO-1 inhibition is considered a valuable anticancer approach. In fact, up-regulation of HO-1 had been repeatedly reported in many types of human malignancies, and in these clinical cases, poor outcomes are reported. To identify novel HO-1 inhibitors suitable for drug development, a scaffold-hopping strategy calculation was utilized to design novel derivatives. Different parts of the selected molecule were analyzed and the different series of novel compounds were virtually evaluated. The calculation for the linker moiety of the classical HO-1 inhibitors structure led us to compounds 5 and 6. A synthetic pathway for the two molecules was designed and the compounds were synthesized. The biological activity revealed an HO-1 inhibition of 0.9 and 54 μM for molecules 5 and 6 respectively. This study suggested that our scaffold-hopping approach was successful and these results are ongoing for further development.
Insights
Novel anticancer drug development targeting heme oxygenase-1 (HO-1) is crucial. This study designed and synthesized novel HO-1 inhibitors using scaffold-hopping, yielding promising compounds for further research.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Oncology
Background:
- Heme oxygenase-1 (HO-1) is frequently upregulated in human malignancies, correlating with poor patient outcomes.
- HO-1 inhibition represents a promising strategy for anticancer drug development.
Purpose of the Study:
- To design and synthesize novel heme oxygenase-1 (HO-1) inhibitors using a scaffold-hopping approach.
- To identify potential drug candidates for anticancer therapies targeting HO-1.
Main Methods:
- Utilized scaffold-hopping computational strategy to design novel HO-1 inhibitor derivatives.
- Synthesized two novel compounds, designated as molecules 5 and 6.
- Assessed the biological activity of the synthesized compounds for HO-1 inhibition.
Main Results:
- Molecule 5 demonstrated potent HO-1 inhibition with an IC50 of 0.9 μM.
- Molecule 6 exhibited HO-1 inhibition with an IC50 of 54 μM.
- The scaffold-hopping strategy proved successful in generating active compounds.
Conclusions:
- The designed novel compounds show potential as anticancer agents targeting HO-1.
- Further development of these compounds is warranted based on promising preliminary results.
- This study validates scaffold-hopping as an effective method for discovering novel enzyme inhibitors.
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