Innovative naphthalene-modified metallosalens: Advancing DNA-targeted strategies for enhanced anticancer efficacy and selectivity

Abstract

Cancer continues to be one of the most challenging diseases to treat due to the limited selectivity of chemotherapeutic agents, the development of resistance, and the toxic side effects associated with many conventional treatments. Despite decades of research and progress in oncology, there remains a pressing need for anticancer agents that are both effective and selective, with reduced toxicity and greater biological specificity. This dissertation addresses these challenges through the rational design, synthesis, and biological evaluation of <strong>novel naphthalene-modified metallosalen complexes</strong>, with the goal of developing a new class of <strong>metal-based anticancer agents</strong> capable of selectively targeting cancer cells through deoxyribonucleic acid (DNA) interactions and apoptosis induction. The central strategy of this research involves the<strong> incorporation of naphthalene groups into the salen ligand framework</strong>, effectively extending the π-conjugated system and improving the ligand's ability to engage in <strong>π–π stacking interactions with DNA base pairs</strong>. This design was guided by the hypothesis that enhanced planarity and extended conjugation would increase the DNA-binding affinity of the complexes, facilitating intercalation and disruption of DNA processes essential for cancer cell survival. The use of <strong>Pt(II)</strong> and <strong>Pd(II)</strong> as central metal ions allows for strong coordination with donor atoms in the salen framework, while also supporting the formation of coordination bonds with nucleic acid sites, contributing to structural distortion of DNA and apoptosis activation.<br /> <br /> This work is structured across five chapters, each contributing to the comprehensive exploration of these metallosalens. <strong>Chapter 1</strong> introduces the motivation for this study, focusing on the challenges associated with current platinum-based chemotherapy drugs such as cisplatin, carboplatin, and oxaliplatin. It highlights the limitations in efficacy due to resistance mechanisms, off-target toxicity, and the need for rationally designed compounds that better target DNA while sparing healthy tissues. <strong>Chapter 2</strong> outlines the design, synthesis, and physicochemical characterization of two novel salen-type ligands (L1 and L2), both bearing naphthalene extensions, and their coordination to Pt(II) and Pd(II) centers to yield four new metal complexes (PtL1, PtL2, PdL1, and PdL2). Structural analysis was performed using UV-Vis spectroscopy, Nuclear Magnetic Resonance (NMR), and single-crystal X-ray diffraction (sc-XRD), which confirmed square planar coordination geometry, successful incorporation of the naphthalene moieties, and minimal geometric distortion-favorable for intercalative DNA interactions. Additionally, lipophilicity (log P_7.4) measurements indicated that PtL1 and PtL2 achieved optimal membrane permeability values, enhancing their drug-like properties. Density Functional Theory (DFT) calculations further characterized their electronic profiles, revealing complementary reactivity and solvation behaviors for L1 and L2, which could influence DNA affinity and bioavailability. <strong>Chapter 3</strong> evaluates the cytotoxicity of the synthesized complexes <em>in vitro</em> using A375 (melanoma), H292 (non-small cell lung cancer), and HSAEC (healthy lung epithelial) cell lines. The results demonstrated that PtL1 showed the highest cytotoxic activity against both cancer cell lines, outperforming the clinically used platinum drugs, with minimal toxicity toward healthy cells. Pd(II) complexes exhibited limited cytotoxicity, under the tested treatment conditions. These findings suggest that increased planarity, optimal lipophilicity, and metal center lability contribute to the selective and potent anticancer activity observed in PtL1 and PtL2. Notably, PtL1's performance positions it as a particularly promising candidate for further development. <strong>Chapter 4</strong> investigates the mechanism of DNA interaction using a combination of UV-Vis spectroscopy, molecular docking (with PDB: 1Z3F), and caspase 3/7 activation assays. The results revealed that all complexes exhibited intercalative binding, with L1 and L2 displaying the strongest interactions due to additional hydrogen bonding capacity. Docking simulations confirmed favorable binding energies and orientations, highlighting π–π stacking and groove-binding as key interaction modes. The apoptotic response was confirmed by the significant activation of caspase-3/7, particularly in cells treated with PtL1 and PtL2. These results support a dual mechanism of action involving DNA intercalation and apoptosis induction. <strong>Chapter 5</strong> proposes future directions to extend the scope and impact of the current work. Planned studies include (1) interaction analyses with human serum albumin (HSA) to assess pharmacokinetics and protein-binding behavior; (2) molecular dynamics simulations to evaluate the stability and interaction energies of the DNA-bound complexes in dynamic environments; (3) co-crystallization with short DNA oligonucleotides, aiming to obtain direct atomic-resolution evidence of binding through X-ray crystallography; and (4) expansion of the project through student-led synthesis of new metal complexes, using more economical and sustainable metal centers such as Cu(II), Fe(III), and Mn(II).<br /> <br /> In conclusion, this dissertation presents a successful example of <strong>rational ligand design integrated with metal coordination chemistry</strong> to create promising anticancer agents. The use of naphthalene-functionalized metallosalens offers a pathway to improve DNA binding, selectivity, and efficacy while maintaining biocompatibility. The comprehensive experimental and computational analysis presented here contributes meaningfully to the field of medicinal inorganic chemistry and significantly advances the pursuit of <strong>next generation of metal-based chemotherapeutics</strong> capable of overcoming the limitations of current treatments.