Naphthalimide Derivatives in Anticancer Therapeutics

Naphthalimide derivatives represent a versatile class of anticancer agents distinguished by a planar aromatic core that facilitates insertion between DNA base pairs and modulation of DNA‐associated enzymes. These compounds can inhibit topoisomerase II activity, generate reactive oxygen species and trigger cell death pathways including apoptosis, autophagy and ferroptosis. Advances in medicinal chemistry have introduced functionalised scaffolds—such as carborane conjugates, triazole linkers, polyamine vectors and macrocyclic assemblies—to improve target selectivity, cellular uptake and subcellular localisation. Many derivatives exhibit intrinsic fluorescence, enabling simultaneous imaging and therapy. Preclinical studies demonstrate potent cytotoxicity against diverse tumour models—from hepatocellular and colorectal carcinomas to lung and sarcoma cell lines—while strategies to harness transporter-mediated uptake aim to reduce systemic toxicity. Structure–activity analyses have revealed how linker length, substitution patterns and hybrid motifs influence DNA binding affinity, cell‐cycle arrest profiles and reactive oxygen species production. Ongoing efforts focus on refining pharmacokinetics, minimising off-target effects and exploiting novel mechanisms such as lysosomal membrane permeabilisation and ferroptosis induction. Collectively, naphthalimide derivatives continue to offer promising avenues for next-generation anticancer therapeutics, combining cytotoxic potency with diagnostic capability.

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Naphthalimide Derivatives in Anticancer Therapeutics publication trend

The graph below shows the total number of articles in naphthalimide derivatives in anticancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Naphthalimide scaffold: A bicyclic aromatic diimide core that intercalates into DNA and serves as a platform for anticancer modifications.

DNA intercalation: Insertion of planar aromatic structures between base pairs, disrupting replication and transcription.

Topoisomerase II inhibition: Blockade of the enzyme responsible for DNA uncoiling, leading to DNA strand breaks.

Reactive oxygen species (ROS): Highly reactive molecules, such as superoxide and hydroxyl radicals, that induce oxidative stress and cell death.

Ferroptosis: An iron‐dependent form of regulated cell death characterised by lipid peroxidation.

Lysosomal membrane permeabilisation: Disruption of lysosome integrity, releasing hydrolytic enzymes that promote cell death.

References

1. Carboranyl-1,8-naphthalimide intercalators induce lysosomal membrane permeabilization and ferroptosis in cancer cell lines. Journal of Enzyme Inhibition and Medicinal Chemistry (2023).
2. Synthesis and in vitro cytotoxic activity of dye-linker-macrocycle conjugates with variable linker length and components. Bioorganic Chemistry (2023).
3. A Polyamine-Based Dinitro-Naphthalimide Conjugate as Substrates for Polyamine Transporters Preferentially Accumulates in Cancer Cells and Minimizes Side Effects in vitro and in vivo. Frontiers in Chemistry (2020).
4. The Synthesis and Antitumor Activity of 1,8-Naphthalimide Derivatives Linked 1,2,3-Triazole. Frontiers in Bioengineering and Biotechnology (2021).
5. Design of DNA Intercalators Based on 4-Carboranyl-1,8-Naphthalimides: Investigation of Their DNA-Binding Ability and Anticancer Activity. International Journal of Molecular Sciences (2022).