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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer
Povilas Kavaliauskas1,2,3,4,5, Felipe Stambuk Opazo6, Waldo Acevedo7
1Department of Organic Chemistry, Kaunas University of Technology, Radvilenu Rd. 19, LT-50254 Kaunas, Lithuania.
Abstract:
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds 9−16 showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood−brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16.
Insights
Novel naphthoquinone derivatives show potent anticancer activity against non-small cell lung cancer (NSCLC) by targeting the COX-2 pathway. Compounds 9 and 16 exhibit significant efficacy and favorable drug-like properties, warranting further investigation for NSCLC treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) is a major global health concern.
- There is an urgent need for novel therapeutic strategies against NSCLC.
- Targeting specific pathways like COX-2 offers a promising approach.
Purpose of the Study:
- To synthesize and characterize novel naphthoquinone derivatives.
- To evaluate their selective anticancer activity against NSCLC.
- To investigate the underlying mechanism of action, including COX-2 mediation.
Main Methods:
- Synthesis of naphthoquinone derivatives (compounds 9-16).
- In vitro anticancer activity testing on A549 NSCLC cells (2D and 3D models).
- Cytotoxicity assessment on non-cancerous Vero cells.
- In silico ADMET profiling and molecular modeling (COX-2 interaction).
Main Results:
- Compounds 9-16 demonstrated structure-dependent anticancer activity against A549 cells.
- Compounds 9 and 16 showed significant reduction in cancer cell viability and induced mitochondrial damage and ROS.
- Promising compounds exhibited lower cytotoxicity to normal Vero cells.
- In silico studies predicted favorable ADMET properties and COX-2 binding for compound 16.
Conclusions:
- Naphthoquinone derivatives, particularly compounds 9 and 16, show significant potential as NSCLC therapeutics.
- The COX-2 pathway is implicated in their anticancer effects.
- Compounds 9 and 16 possess favorable drug-like properties and warrant further in vivo evaluation.
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