Bioorganic chemistry · 2026
Synthesis of thiadiazole derivatives and investigation of the effects against colon cancer cells.
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Xu Zhiping, Shang Shu, Yu Wenli, Li Yingying, Zhang Jian, Zhao Zhibo, Shang Xinyue, Sun Chiyu
Аннотация
OBJECTIVE: Colon cancer is a life-threatening gastrointestinal malignancy in which Hedgehog (Hh) signaling plays a critical role, yet no Hh pathway inhibitor is clinically approved for its treatment. This study aimed to design and synthesize thiadiazole-based Hh pathway inhibitors and evaluate their anti-colon cancer activity and mechanism.
METHODS: A series of thiadiazole derivatives were synthesized from pyrazole boronic acid and 2,5-dibromothiadiazole via nucleophilic substitution, Suzuki-Miyaura coupling, and tert-butoxycarbonyl deprotection, with structures confirmed by 1H NMR, 13C NMR, and mass spectrometry. Dual-luciferase reporter assay was used to screen for the more potent Hedgehog inhibitor, and BODIPY-cyclopamine competitive binding, molecular docking, and molecular dynamics simulations were employed to assess smoothened binding. MTT assay determined antiproliferative activity and dosing concentrations. Wound healing, transwell, and flow cytometry assays evaluated migration, invasion, apoptosis, and cell cycle effects, while Western blot and RT-qPCR examined Hh pathway-related protein and gene expression.
RESULTS: The target compounds were structurally confirmed. SEZ13 exhibited the strongest Hedgehog inhibition, outperforming Vismodegib. BODIPY-cyclopamine assay, molecular docking, and molecular dynamics simulations confirmed its binding to smoothened. SEZ13 dose-dependently inhibited HCT116 and HT-29 cell proliferation. At 30 μM, SEZ13 significantly suppressed migration and invasion, induced apoptosis, and caused G2/M arrest (P < 0.05). Mechanistically, SEZ13 significantly downregulated Gli1 and Patched-1 mRNA and Gli1 protein expression (P < 0.05).
CONCLUSION: SEZ13, a novel thiadiazole derivative, binds smoothened and exerts anti-colon cancer activity by inhibiting the Hedgehog/Gli1 signaling pathway.
METHODS: A series of thiadiazole derivatives were synthesized from pyrazole boronic acid and 2,5-dibromothiadiazole via nucleophilic substitution, Suzuki-Miyaura coupling, and tert-butoxycarbonyl deprotection, with structures confirmed by 1H NMR, 13C NMR, and mass spectrometry. Dual-luciferase reporter assay was used to screen for the more potent Hedgehog inhibitor, and BODIPY-cyclopamine competitive binding, molecular docking, and molecular dynamics simulations were employed to assess smoothened binding. MTT assay determined antiproliferative activity and dosing concentrations. Wound healing, transwell, and flow cytometry assays evaluated migration, invasion, apoptosis, and cell cycle effects, while Western blot and RT-qPCR examined Hh pathway-related protein and gene expression.
RESULTS: The target compounds were structurally confirmed. SEZ13 exhibited the strongest Hedgehog inhibition, outperforming Vismodegib. BODIPY-cyclopamine assay, molecular docking, and molecular dynamics simulations confirmed its binding to smoothened. SEZ13 dose-dependently inhibited HCT116 and HT-29 cell proliferation. At 30 μM, SEZ13 significantly suppressed migration and invasion, induced apoptosis, and caused G2/M arrest (P < 0.05). Mechanistically, SEZ13 significantly downregulated Gli1 and Patched-1 mRNA and Gli1 protein expression (P < 0.05).
CONCLUSION: SEZ13, a novel thiadiazole derivative, binds smoothened and exerts anti-colon cancer activity by inhibiting the Hedgehog/Gli1 signaling pathway.