Design and Synthesis of New Combretastatin A-4 Derivatives Containing Naphthothiophene Based on the Structural Rigidification Strategy
Main Article Content
Abstract
Six new combretastatin A-4 derivatives containing a naphtho[2,3-b]thiophene-4,9-dione core were successfully synthesized via a two-step procedure. This approach involved a multi-component reaction to generate dihydrofuranonaphthoquinone intermediates, followed by a sulfur-mediated oxidative transformation of the dihydrofuran scaffold into the corresponding thiophene derivatives. The structures of all synthesized compounds were characterized using IR, ¹H-NMR, and ¹³C-NMR spectroscopy. In vitro cytotoxicity assays against the A549 lung cancer cell line revealed that five out of the six derivatives exhibited moderate to strong growth inhibitory activity, with IC₅₀ values ranging from 3.40 ± 0.24 to 46.46 ± 1.63 µM. Notably, the fluorinated analogues 4b and 4c demonstrated the most potent cytotoxicity, with IC₅₀ values of 3.40 ± 0.24 and 3.69 ± 0.35 µM, respectively. Molecular docking simulations indicated that compound 4c accommodates effectively within the colchicine-binding site (CBS) of tubulin through a cooperative multi-point interaction mechanism, where polar anchoring and hydrophobic packing work synergistically to stabilize the ligand–protein complex. Despite satisfying standard drug-likeness criteria, computational ADME profiling highlighted that the high hydrophobicity and poor water solubility of 4c remain major physicochemical hurdles. Overall, these combretastatin A-4 derivatives represent a novel class of bioactive scaffolds with promising potential for further structural optimization in anticancer drug development.
Keywords:
Combretastatin A-4 derivatives; Naphtho[2,3-b]thiophene-4,9-dione; Structural rigidification; A549 cytotoxicity; Colchicine-binding site; Molecular docking; ADME profiling.
References
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[17] H. T. Nguyen, H. P. The, A. N. Tuan, H. N. T. Thu, T. A. D. Thi, G. L. N. Thuy, P. H. Thi, Q.G. N. Thi, T. V. Nguyen, Improved Synthesis, Molecular Modeling and Anti-inflammatory Activity of New Fluorinated Dihydrofurano-naphthoquinone Compounds, Bioorg. Med. Chem. Lett, Vol. 104, 2024, pp. 129714,
https://doi.org/10.1016/j.bmcl.2024.129714.
[18] H. T. Nguyen, G. L. N. Thuy, P. Hoang Thi, Q. G. N. Thi, T. A. Nguyen, T. H. Nguyen Thi, T. A. D. Thi, T. V. Nguyen, Microwave-assisted Three-component Synthesis of Novel N-arylated-dihydrobenzo[g]quinoline-5,10-diones and Their Potential Cytotoxic Activity, Chem. Biodivers, Vol. 19, 2024, pp. e202200359,
https://doi.org/10.1002/cbdv.202200359.
[19] H. T. Nguyen, Q. G. N. Thi, T. H. N. Thi et al., Synthesis and Biological Activity, and Molecular Modelling Studies of Potent Cytotoxic Podophyllotoxin-naphthoquinone Compounds, RSC Adv, Vol. 12, 2022, pp. 22004-22019, https://doi.org/10.1039/D2RA03312G.
[20] A. E. Prota, F. Danel, F. Bachmann F et al., The Novel Microtubule-destabilizing Drug BAL27862 Binds to the Colchicine Site of Tubulin with Distinct Effects on Microtubule Organization, J. Mol. Biol, Vol. 426, 2014, pp. 1848-1860, https://doi.org/10.1016/j.jmb.2014.02.005.
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[22] H. T. Nguyen, H. N. Van, H. P. The et al., Synthesis, Molecular Docking Analysis, and in Vitro Cytotoxic Evaluation of New Fluorinated γ-butyrolactone-aza-anthraquinone Compounds, Chem, Biodivers, Vol. 22, 2025, pp. e02030, https://doi.org/10.1002/cbdv.202502030.
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https://doi.org/10.1021/jm020017n.
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