Design and Synthesis of New Coumarin Hybrids Active Against Drug-Sensitive and Drug-Resistant Neuroblastoma Cells
Carola Grondona1, Barbara Marengo2,3, Giulia Elda Valenti2
1Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, I-16132 Genoa, Italy.
Abstract:
High-risk neuroblastoma (NB) is an aggressive pediatric tumor characterized by pronounced biological heterogeneity and frequent development of chemoresistance, which critically limits therapeutic efficacy. Identifying novel anti-NB agents remains an urgent unmet need. To address this, we designed and synthesized 17 hybrid molecules by combining natural antioxidant scaffolds (coumarin, vanillin, and isovanillin) through an acyl-hydrazone linker. Several derivatives significantly reduced the viability of MYCN-amplified NB cells (HTLA-230) and their multi-drug resistant counterpart (ER) while not affecting human keratinocytes (HaCat). Among them, compounds 5, 9 and 12 selectively inhibited HTLA and ER growth (10-25%) without affecting HaCat, accompanied by robust ROS overproduction, particularly by 9 and 12 (up to 40%). None of these compounds induced apoptosis or ferroptosis. Instead, their antiproliferative effects were associated with senescence induction and, only for compound 5, with a decrease in clonogenic potential. Moreover, to further characterize compounds 5, 9, and 12, the analysis was extended across other human neuroblastoma cell lines. In parallel, the effects of the compounds on non-malignant cell lines were assessed to obtain an indication of their selectivity toward tumor cells. Compound 17, a structural analog lacking the second aromatic ring in the ex-aldehyde portion, displayed a distinct profile with a limited anticancer activity, underscoring the importance of this structural fragment for antiproliferative efficacy.
Insights
Novel hybrid molecules targeting neuroblastoma (NB) show promise. Compounds 5, 9, and 12 selectively inhibit NB cell growth by inducing senescence and reactive oxygen species (ROS), offering new therapeutic avenues for this aggressive pediatric cancer.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pediatric Cancer Research
Background:
- High-risk neuroblastoma (NB) is a challenging pediatric cancer with significant chemoresistance.
- Developing novel therapeutic agents against NB is a critical unmet need.
Purpose of the Study:
- To design and synthesize novel hybrid molecules combining natural antioxidant scaffolds for anti-neuroblastoma activity.
- To evaluate the efficacy and selectivity of these compounds against NB cell lines.
Main Methods:
- Synthesis of 17 hybrid molecules incorporating coumarin, vanillin, or isovanillin scaffolds via an acyl-hydrazone linker.
- Assessment of cell viability, reactive oxygen species (ROS) production, apoptosis, ferroptosis, senescence, and clonogenic potential in NB and non-malignant cell lines.
- Structure-activity relationship analysis, including evaluation of a key structural analog (compound 17).
Main Results:
- Compounds 5, 9, and 12 selectively inhibited the growth of MYCN-amplified and multi-drug resistant NB cells (HTLA-230, ER) without affecting normal keratinocytes (HaCat).
- These active compounds induced significant ROS overproduction, particularly compounds 9 and 12.
- Antiproliferative effects were primarily mediated by senescence induction, with compound 5 also reducing clonogenic potential; apoptosis and ferroptosis were not induced.
- Compound 17, lacking a specific structural fragment, showed limited anticancer activity, highlighting the importance of this moiety.
Conclusions:
- Novel hybrid molecules based on natural antioxidants demonstrate potent and selective antiproliferative activity against high-risk neuroblastoma.
- Compounds 5, 9, and 12 represent promising lead candidates for further development as anti-NB agents, acting through senescence induction and ROS generation.
- The structural integrity of the hybrid molecules is crucial for their efficacy, as indicated by the reduced activity of compound 17.
Related Concept Videos
01:28Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
01:29Drugs Affecting Neurotransmitter Synthesis
01:14Design Example: Resistive Touchscreen
When a user touches the screen, the two layers make contact at a specific point known as the touchpoint. This contact reduces the resistance between...
01:14Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug
01:20Antiepileptic Drugs: Potassium Channel Activators
Ezogabine has gained approval as an adjunctive treatment...
01:22Biopharmaceutical Factors Influencing Drug Product Design: Overview