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Published on: February 9, 2021
Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro
Sebastian Braun1, Svetlana Paskaš2, Markus Laube3
1Institut für Anorganische Chemie, Universität Leipzig, Johannisallee 29, 04103, Leipzig, Germany.
Abstract:
The presence of inflammatory mediators in the tumor microenvironment, such as cytokines, growth factors or eicosanoids, indicate cancer-related inflammatory processes. Targeting these inflammatory mediators and related signal pathways may offer a rational strategy for the treatment of cancer. This study focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic dicarba-closo-dodecaboranes (carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. The di-tert-butylphenol derivative tebufelone represents a selective dual COX-2/5-LO inhibitor. The incorporation of meta- or para-carborane into the tebufelone scaffold resulted in eight carborane-based tebufelone analogs that show no COX inhibition but 5-LO inhibitory activity in vitro. Cell viability studies on HT29 colon adenocarcinoma cells revealed that the observed antiproliferative effect of the para-carborane analogs of tebufelone is enhanced by structural modifications that include chain elongation in combination with introduction of a methylene spacer resulting in higher anticancer activity compared to tebufelone. Hence, this strategy proved to be a promising approach to design potent 5-LO inhibitors with potential application as cytostatic agents.
Insights
Researchers developed novel carborane-based compounds targeting 5-lipoxygenase (5-LO) to combat cancer. These potent 5-LO inhibitors show promising anticancer activity, offering a new strategy for cytostatic agent development.
Area of Science:
- Oncology
- Medicinal Chemistry
- Biochemistry
Background:
- Cancer-related inflammation involves mediators like cytokines and eicosanoids.
- Targeting inflammatory pathways presents a viable cancer treatment strategy.
- Eicosanoids are synthesized by key enzymes cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO).
Purpose of the Study:
- To design and synthesize novel carborane-containing analogs of the dual COX-2/5-LO inhibitor tebufelone.
- To evaluate the in vitro inhibitory activity of these analogs against COX and 5-LO enzymes.
- To assess the antiproliferative and anticancer effects of the most promising compounds in colon adenocarcinoma cells.
Main Methods:
- Incorporation of metabolically stable, hydrophobic dicarba-closo-dodecaboranes (carboranes) into the tebufelone scaffold.
- Synthesis of eight carborane-based tebufelone analogs.
- In vitro enzyme inhibition assays for COX and 5-LO.
- Cell viability studies using HT29 colon adenocarcinoma cells.
Main Results:
- Carborane-tebufelone analogs exhibited no COX inhibition but demonstrated significant 5-LO inhibitory activity in vitro.
- Para-carborane analogs, particularly those with chain elongation and a methylene spacer, showed enhanced antiproliferative effects.
- These modified analogs displayed higher anticancer activity compared to the parent compound, tebufelone.
Conclusions:
- The strategy of incorporating carboranes into tebufelone is effective for designing potent 5-LO inhibitors.
- Modified carborane-tebufelone analogs show significant potential as cytostatic agents for cancer therapy.
- This approach offers a promising avenue for developing novel anticancer therapeutics targeting 5-LO pathways.
