Design, microwave-assisted domino synthesis, and biological evaluation of novel naphtho[2,3-b]furan-4,9-diones as rigidified combretastatin A-4 analogs inducing G0/G1 cell cycle arrest and apoptosis
4 affiliations
- 1Graduate University of Science and Technology, VAST 18 Hoang Quoc Viet, Nghia Do Hanoi Vietnam
- 2Institute of Chemistry, Vietnam Academy of Science and Technology (VAST) 18 Hoang Quoc Viet, Nghia Do Hanoi Vietnam
- 3Hanoi Medicial College 35 Doan Thi Diem, O Cho Dua Hanoi Vietnam
- 4Novalix Chau. du Vexin 27100 Val-de-Reuil France
Abstract
A novel series of fourteen fluorinated naphtho[2,3-b]furan-4,9-dione derivatives (5a–n) was designed, synthesized, and structurally mapped as conformational equivalents of the microtubule-disrupting agent combretastatin A-4 (CA-4). The core medicinal chemistry strategy relied on replacing the highly flexible exo-ethylene linker of native CA-4 with a rigid carbonyl lock at the C-2 position of the furan ring, thereby restricting rotatable bonds and freezing the peripheral aromatic rings into a stable cis-like bioactive orientation. One aryl domain was substituted with an electron-deficient naphthoquinone core to maximize target pocket engagement. These target compounds were efficiently synthesized in good yields (69–81%) via a microwave-assisted three-component reaction utilizing 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, pyridinium bromides, and 1,4-diazabicyclo[2.2.2]octane as a base catalyst. Cytotoxicity screening demonstrated that this structural rigidification maintained antiproliferative profiles across human cancer cells (KB, HepG2, A549, and MCF7), with compound 5c emerging as the most potent compound exhibiting IC50 values ranging from 1.90 to 11.48 µM. Flow cytometric analysis showed that compound 5c induced concentration-dependent cell cycle arest at G0/G1 phase and apoptosis in A549 cells. Molecular docking and density functional theory simulations predicted that 5c establishes a highly stable interaction network within the colchicine binding site of the α,β tubulin interface. Collectively, these findings highlight compound 5c as a highly promising preliminary cytotoxic lead for the development of novel anticancer agents.
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BibTeX
@article{nguyen2026design,
title = {{Design, microwave-assisted domino synthesis, and biological evaluation of novel naphtho[2,3-b]furan-4,9-diones as rigidified combretastatin A-4 analogs inducing G0/G1 cell cycle arrest and apoptosis}},
author = {Tuan Anh Nguyen and Ha Thanh Nguyen and Nga Nguyen Thi and Giang Le-Nhat-Thuy and Quynh Giang Nguyen Thi and Phuong Hoang Thi and Mai Dang Thi and Julien Braire and Tu Anh Le Thi and Van Anh Pham Thi and Xuan Nhiem Nguyen and Tuyen Van Nguyen},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra08348j},
url = {https://europepmc.org/article/PMC/PMC13660020},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Design, microwave-assisted domino synthesis, and biological evaluation of novel naphtho[2,3-b]furan-4,9-diones as rigidified combretastatin A-4 analogs inducing G0/G1 cell cycle arrest and apoptosis
AU - Tuan Anh Nguyen
AU - Ha Thanh Nguyen
AU - Nga Nguyen Thi
AU - Giang Le-Nhat-Thuy
AU - Quynh Giang Nguyen Thi
AU - Phuong Hoang Thi
AU - Mai Dang Thi
AU - Julien Braire
AU - Tu Anh Le Thi
AU - Van Anh Pham Thi
AU - Xuan Nhiem Nguyen
AU - Tuyen Van Nguyen
PY - 2026
DA - 2026/10/13
JO - RSC advances
DO - 10.1039/d6ra08348j
UR - https://europepmc.org/article/PMC/PMC13660020
AB - A novel series of fourteen fluorinated naphtho[2,3-b]furan-4,9-dione derivatives (5a–n) was designed, synthesized, and structurally mapped as conformational equivalents of the microtubule-disrupting agent combretastatin A-4 (CA-4). The core medicinal chemistry strategy relied on replacing the highly flexible exo-ethylene linker of native CA-4 with a rigid carbonyl lock at the C-2 position of the furan ring, thereby restricting rotatable bonds and freezing the peripheral aromatic rings into a stable cis-like bioactive orientation. One aryl domain was substituted with an electron-deficient naphthoquinone core to maximize target pocket engagement. These target compounds were efficiently synthesized in good yields (69–81%) via a microwave-assisted three-component reaction utilizing 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, pyridinium bromides, and 1,4-diazabicyclo[2.2.2]octane as a base catalyst. Cytotoxicity screening demonstrated that this structural rigidification maintained antiproliferative profiles across human cancer cells (KB, HepG2, A549, and MCF7), with compound 5c emerging as the most potent compound exhibiting IC50 values ranging from 1.90 to 11.48 µM. Flow cytometric analysis showed that compound 5c induced concentration-dependent cell cycle arest at G0/G1 phase and apoptosis in A549 cells. Molecular docking and density functional theory simulations predicted that 5c establishes a highly stable interaction network within the colchicine binding site of the α,β tubulin interface. Collectively, these findings highlight compound 5c as a highly promising preliminary cytotoxic lead for the development of novel anticancer agents.
SN - 2046-2069
ER -