Engineered Artesunate-Naphthalimide Hybrid Dual Drug for Synergistic Multimodal Therapy against Experimental Murine
Debapriya RoyMahapatra1, Ranjeet Singh2, Ugir Hossain Sk1
1Department of Clinical and Translational Research, Chittaranjan National Cancer Institute, Kolkata 700 026, West Bengal, India.
Abstract:
Lymphoma can effectively be treated with a chemotherapy regimen that is associated with adverse side effects due to increasing drug resistance, so there is an emergent need for alternative small-molecule inhibitors to overcome the resistance that occurs in lymphoma management and overall increase the prognosis rate. A new series of substituted naphthalimide moieties conjugated via ester and amide linkages with artesunate were designed, synthesized, and characterized. In addition to the conjugates, to further achieve a theranostic molecule, FITC was incorporated via a multistep synthesis process. DNA binding studies of these selected derivatives by ultraviolet-visible (UV-vis), fluorescence spectroscopy, intercalating dye (EtBr, acridine orange)-DNA competitive assay, and minor groove binding dye Hoechst 33342-DNA competitive assay suggested that the synthesized novel molecules intercalated between the two strands of DNA due to its naphthalimide moiety and its counterpart artesunate binds with the minor groove of DNA. Napthalimide-artesunate conjugates inhibit the growth of lymphoma and induce apoptosis, including ready incorporation and reduction in cell viability. The remodeled drug has a significant tumoricidal effect against solid DL tumors developed in BALB/c mice in a dose-dependent manner. The novel drug appears to inhibit metastasis and increase the survival of the treated animals compared with untreated littermates.
Insights
New naphthalimide-artesunate conjugates show promise in treating lymphoma by inhibiting tumor growth and metastasis. These novel small-molecule inhibitors offer a potential alternative to chemotherapy, improving lymphoma management and patient survival rates.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Chemotherapy for lymphoma faces challenges with drug resistance and adverse effects.
- There is a critical need for novel small-molecule inhibitors to improve lymphoma treatment outcomes.
- Developing theranostic agents can enhance lymphoma management and patient prognosis.
Purpose of the Study:
- To design, synthesize, and characterize novel naphthalimide-artesunate conjugates.
- To investigate the DNA binding properties and mechanism of action of these derivatives.
- To evaluate the efficacy of these conjugates as potential anti-lymphoma agents.
Main Methods:
- Synthesis and characterization of substituted naphthalimide-artesunate conjugates, including FITC incorporation.
- DNA binding studies using UV-vis, fluorescence spectroscopy, and competitive dye-DNA assays.
- In vitro assessment of cytotoxicity and apoptosis induction in lymphoma cells.
- In vivo evaluation of anti-tumor activity against solid DL tumors in mice.
Main Results:
- Synthesized novel molecules intercalate into DNA via the naphthalimide moiety and bind the minor groove via artesunate.
- Naphthalimide-artesunate conjugates effectively inhibit lymphoma cell growth and induce apoptosis.
- The remodeled drug demonstrated significant dose-dependent tumoricidal effects against solid DL tumors in mice.
- The novel drug inhibited metastasis and increased survival rates in treated animals.
Conclusions:
- Naphthalimide-artesunate conjugates represent a promising new class of small-molecule inhibitors for lymphoma.
- These agents exhibit potent anti-lymphoma activity through DNA interaction and apoptosis induction.
- The developed theranostic molecule shows potential for improved lymphoma treatment and patient survival.
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