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Life sciences · Journal article
Scientific Reports · September 9, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a preclinical chemical synthesis and structure-activity study identifying a novel hexahydroacridine derivative (compound 4d) with in vitro cytotoxicity against lung and other cancer cell lines and predicted multi-target kinase binding. The work establishes a chemical scaffold and mechanistic hypothesis but remains far from clinical relevance; substantial additional preclinical and in vivo validation would be required before any therapeutic claim can be tested.
In vitro cytotoxicity screening and molecular docking study. Five human cancer cell lines (H460 lung cancer, A431 epidermoid carcinoma, A549 lung adenocarcinoma, MDA-MB-231 triple-negative breast cancer) and HSF normal human skin fibroblasts.. Intervention: Hexahydroacridine derivatives with N-aryl substituents and C-9 biphenyl or 4-bromophenyl groups; lead compound 4d featured fluorine substitution for metabolic stability.. Compared with: Untreated control cells and normal fibroblasts (HSF) for selectivity index calculation..
Compound 4d demonstrated IC₅₀ of 17.91 ± 2.8 µg/mL against H460 lung cancer cells with selectivity index of 20.7 versus normal fibroblasts (HSF) Molecular docking predicted strong binding affinities: TOP2B (−7.02 kcal/mol), p38 MAPK (−7.05 kcal/mol), p53 (−7.25 kcal/mol), EGFR (−6.55 kcal/mol) MM-GBSA binding free energy for 4d–EGFR complex estimated at ΔG bind ≈ −42 kcal/mol
No information on metabolic stability, pharmacokinetics, bioavailability, off-target binding, or drug-like properties (ADME) provided.
This work presents a novel chemical scaffold and identifies a putative multi-target kinase inhibitor at the earliest discovery stage. Clinicians and researchers should view this as a proof-of-concept requiring extensive preclinical validation (in vivo efficacy, toxicology, pharmacokinetics, selectivity confirmation, and off-target activity profiling) before any therapeutic potential can be assessed.
Early-stage in vitro screening of novel synthetic compounds with in silico validation; no in vivo efficacy, pharmacokinetics, or toxicology data reported; single lead compound identified but requires substantial further development.
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Quoted from the source exactly as published.
This work presents a novel chemical scaffold and identifies a putative multi-target kinase inhibitor at the earliest discovery stage. Clinicians and researchers should view this as a proof-of-concept requiring extensive preclinical validation (in vivo efficacy, toxicology, pharmacokinetics, selectivity confirmation, and off-target activity profiling) before any therapeutic potential can be assessed.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract Despite advances in targeted cancer therapies, drug resistance and off-target toxicity remain major challenges, underscoring the need for new multi-targeted agents with improved selectivity. The present study evaluated the anticancer potential of newly synthesized hexahydro-1,8-acridinedione derivatives featuring strategic structural modifications at positions 9 and 10. The novelty of this work lies in the introduction of N -aryl substituents combined with C-9 biphenyl or 4-bromophenyl groups, a structural motif not previously reported for this chemotype. This dual modification was rationally designed to enhance π-π stacking interactions with kinase ATP-binding pockets while improving metabolic stability through fluorine substitution. Compounds were synthesized via a one-pot multicomponent reaction catalyzed by PTSA and characterized by IR, 1 H/ 13 C NMR, and LC–MS. Guided by structure-based design principles, five derivatives ( 4a, 4d, 4f., 5a, 5b ) were evaluated for cytotoxicity against HSF, H460, A431, A549, and MDA-MB-231 cell lines. Compound 4d emerged as the most potent, with an IC₅₀ of 17.91 ± 2.8 µg/mL against H460 lung cancer cells and a high selectivity index (SI = 20.7), in addition to exhibiting a considerable anti-telomerase activity. Molecular docking revealed strong binding affinities of 4d with TOP2B (− 7.02 kcal/mol), p38 MAPK (− 7.05 kcal/mol), p53 (− 7.25 kcal/mol), and EGFR (− 6.55 kcal/mol), supported by MM-GBSA binding free energies (ΔG bind ≈ − 42 kcal/mol for 4d–EGFR). Furthermore, 100-ns Molecular Dynamics simulations confirmed the stability of the 4d -EGFR complex (RMSD ≈ 1.31 Å; persistent H-bonds with CYS773/GLN767). These findings establish compound 4d as a promising multi-target lead scaffold, warranting further optimization toward selective anticancer therapeutics.
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