The persistent threat posed by cancer and the emergence of chemoresistance necessitate the development of novel therapeutics, positioning quinoline derivatives as privileged scaffolds in oncology. This review systematically consolidates recent advances (2019–2025) in Structure- Activity Relationships (SARs) and molecular mechanisms governing the antitumor efficacy of quinoline-based compounds. We focus on structure-activity relationship analysis of kinase inhibitors (targeting EGFR, MEK1, etc.), topoisomerase inhibitors, Tubulin Polymerization Inhibitors, mitochondrial/lysosomal targeting agents (inducing oxidative stress and organelle damage), and DNA-damaging agents (metal ligands or those causing DNA breaks). Structure-activity relationship studies indicate that the structural modification strategies corresponding to different mechanisms vary significantly, and the position of substituents, electronic effects, and scaffold transitions are crucial for drug efficacy. This review provides a rational blueprint for designing next-generation anticancer agents with enhanced efficacy and reduced systemic toxicity, thereby accelerating future drug development.
Abstract: Chimeric Antigen Receptor (CAR)-engineered immune cells now extend well beyond autologous CAR-T therapy to span early-clinical NK, invariant natural killer T, gamma-delta T, and double-negative T platforms, clinical-stage regulatory T-cell programs, preclinical macrophage, neutrophil and dendritic-cell systems, and adjacent BCR/antibody-engineered B-cell approaches. This Perspective proposes a chassis-aware framework in which target biology and tissue location determine the required effector function, and this function in turn constrains cell source, receptor architecture and antigen logic, engineering route, developability assays, and safety controls, rather than allowing receptor design to be transferred unchanged from the CD19 CAR-T precedent. Each chassis requires a lineage-adapted signalling architecture, and ex vivo and in vivo programming are treated as distinct pharmacological strategies with different implications for expression duration, biodistribution, off-target transduction, redosing, and rescue. Clinical translation further requires chassis- and route-specific potency assays, predefined critical quality attributes, batch comparability, quantitative biodistribution and persistence measurements, and controls for lineage instability or suppressive polarization. Treating each chassis-route combination as a distinct therapeutic hypothesis, rather than a variant of CAR-T, provides a testable and generalizable route from molecular design to clinical and regulatory development.
Introduction: While olanzapine is an effective atypical antipsychotic, its clinical application is limited by adverse effects such as weight gain and lipid metabolism disorders. Berberine, a natural compound known for its lipid-lowering and anti-inflammatory properties, presents a potential therapeutic strategy to counteract these issues. Therefore, this study aimed to explore the ameliorative impact of berberine on olanzapine-induced lipid metabolism disorders in mice, with a specific focus on the AMPK–PPARα–CD36 signaling axis. materials and methods: Male C57 mice were divided into control, olanzapine, and olanzapine + berberine groups, treated for 6 weeks. Plasma TG, TC, HDL-C, and LDL-C were measured. Liver tissues were stained for lipid accumulation. Hub genes were identified through PubMed searches, differential analysis, weighted gene co-expression network analysis, and SVM-RFE. Protein expressions of AMPK, p-AMPK, PPARα, and CD36 were assessed by Western blot. Methods: Male C57 mice were divided into control, olanzapine, and olanzapine + berberine groups, treated for 6 weeks. Plasma TG, TC, HDL-C, and LDL-C were measured. Liver tissues were stained for lipid accumulation. Hub genes were identified through PubMed searches, differential analysis, weighted gene co-expression network analysis, and SVM-RFE. Protein expressions of AMPK, p-AMPK, PPARα, and CD36 were assessed by Western blot. Results: Olanzapine increased plasma TG and HDL-C, decreased TC and LDL-C, and caused hepatic lipid accumulation. It also downregulated AMPK/p-AMPK and PPARα, while upregulating CD36. Berberine reversed these effects, lowering TG, partially restoring TC and LDL-C, reducing liver lipid deposition, increasing AMPK/p-AMPK and PPARα, and inhibiting CD36 expression. Discussion: Olanzapine-induced lipid dysregulation may be mediated by the inhibition of AMPK and PPARα and the upregulation of CD36. Berberine effectively reversed these changes by activating the AMPK-PPARα pathway and inhibiting CD36 expression, thereby improving hepatic lipid accumulation. These findings suggest that berberine may serve as a potential adjunctive therapy for alleviating olanzapine-induced metabolic side effects. Conclusion: Olanzapine induces lipid disorders by inhibiting AMPK, reducing PPARα, and upregulating CD36, enhancing lipid uptake and impairing fatty acid oxidation. Berberine ameliorates these abnormalities by activating AMPK–PPARα signaling and suppressing CD36, highlighting its potential as an adjunctive therapy to mitigate olanzapine-induced metabolic side effects.
Introduction: An important regulatory aspect of cancer progression is the interaction between p53 and MDM2, particularly in breast cancer, where the excessive presence of MDM2 hampers p53's tumour- suppressing function. Although many natural flavonoids are recognized for their influence on this pathway, they often exhibit suboptimal potency and pharmacokinetic properties. To discover flavonoid derivatives with stronger inhibitory effects on the p53–MDM2 interaction, this research integrates Density Functional Theory (DFT), molecular docking, and AI-enhanced de novo optimization. Materials and Methods: Validated molecular docking protocols were employed to evaluate 52 flavonoids from the Indonesian Natural Products Database against the p53–MDM2 complex, yielding a validation RMSD value of 0.4935 Å. AI-assisted molecular design was subsequently applied to the topperforming compounds to generate optimized derivatives with improved binding affinity and pharmacokinetic properties. Binding interactions were analyzed using conventional molecular visualization approaches. Drug-likeness, ADME, and toxicity profiles were predicted using SwissADME, ProTox-II, and ADMETlab 2.0. Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d,p) level were performed to evaluate electronic properties and molecular stability. Furthermore, Molecular Dynamics (MD) simulations and MM-GBSA calculations were conducted to investigate the dynamic stability and binding free energy of the selected complexes. Results: Among the AI-optimized derivatives, Amentoflavone-1 demonstrated the strongest binding affinity (–5.60 kcal/mol), outperforming Resveratrol (–4.24 kcal/mol). Interaction profiling revealed that hydrophobic interactions and π–π stacking with key residues within the p53-MDM2 binding pocket were the primary stabilizing forces. ADME predictions indicated improved drug-likeness and absorption properties, while toxicity analyses suggested reduced mutagenicity and mitochondrial toxicity, though a moderate hepatotoxicity risk remained. DFT calculations demonstrated favourable HOMO– LUMO energy gaps and frontier molecular orbital characteristics associated with molecular stability and chemical reactivity. Molecular dynamics simulations over 100 ns showed that the p53-MDM2– Amentoflavone-1 complex maintained a stable conformation comparable to the native ligand, as evidenced by RMSD, RMSF, SASA, and radius-of-gyration analyses. In addition, MM-GBSA calculations revealed a binding free energy of –18.37 kcal/mol for Amentoflavone-1, confirming spontaneous and thermodynamically favourable binding to the p53-MDM2 complex. Discussion: The integration of AI-driven de novo design with conventional computational modelling successfully enhanced and clarified the pharmacological potential of flavonoid scaffolds. Amentoflavone- 1 exhibited favourable binding interactions consistent with known p53–MDM2 inhibition mechanisms, supported by stable molecular dynamics behaviour and thermodynamically favourable binding profiles. Improvements in ADME and toxicity parameters further suggest that AI-guided structural modification can effectively optimize flavonoid-based inhibitor candidates. Conclusion: Overall, AI-guided structural optimization improved the binding characteristics, molecular stability, and drug-likeness profile of Amentoflavone-1 relative to its parent compound. Although its binding affinity and MM-GBSA energy remained lower than those of the native ligand, Amentoflavone- 1 demonstrated stable interactions with the p53-MDM2 complex and should be considered a promising preliminary lead compound for further structural refinement and experimental validation.
Introduction: Worldwide, breast cancer is one of the top cancers diagnosed on a global scale. Mānuka honey (MH) and honey sugar analogue (HSA) are being studied for their potential to prevent breast cancer. Materials and Methods: A total of 60 Female albino rats were classified into six groups. Group I (negative control group). Group II (MH): rats were administered MH (1.0 g/kg) daily via an oral tube for 120 days. Group III (HSA): rats were administered HSA (1.0 g/kg) daily via an oral tube for 120 days. Group IV (DMBA): rats were treated with a single dose of DMBA (80 mg/kg) via oral tube to induce breast cancer. Group V (DMBA + MH) & Group VI (DMBA + HSA): rats were treated with MH (1.0 g/kg) and HSA (1.0 g/kg), respectively, via oral tube, then received a single dose of DMBA the next day, and treatment with MH & HSA continued until 120 days. Results: Oral administration of MH and HSA improved most hematological parameters. Additionally, we also found a significant suppression in Estradiol (E2) and a clear decrease in caspase- 3, MDA, and mTOR) values in mammary gland tissue samples compared to DMBA-induced rats. Furthermore, BRCA1 expression was increased in both MH and HSA groups, and a marked downregulation of AKT was observed in our treated groups. Our findings were supported by histopathological examination of mammary gland tissue. Discussion: This study highlights the potential of daily oral administration of MH and HSA to exert antioxidant and antitumor effects and to modulate apoptosis-related signaling pathways in DMBA-induced rats. Conclusion: MH and HSA demonstrated promising chemopreventive and protective effects against DMBA-induced mammary carcinogenesis, warranting further studies to evaluate their potential role in breast cancer prevention.
