2. Academic Validation
  3. Design and bio-evaluation of novel millepachine derivatives targeting tubulin colchicine binding site for treatment of osteosarcoma

Design and bio-evaluation of novel millepachine derivatives targeting tubulin colchicine binding site for treatment of osteosarcoma

  • Bioorg Chem. 2024 Jul 9:151:107624. doi: 10.1016/j.bioorg.2024.107624.
Dawei Geng 1,  Zhong Chen 2,  Yin Li 3,  Tianbao Liu 4,  Liming Wang 5
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
  • 2 Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
  • 3 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Provincial Hospital, Jinan 250021, China.
  • 4 Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
  • 5 Department of Orthopaedics, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China. Electronic address: limingwang2024@163.com.
PMID: 39002514 DOI: 10.1016/j.bioorg.2024.107624
Abstract

Microtubules are recognized as an appealing target for Cancer treatment. We designed and synthesized of novel tubulin colchicine binding site inhibitors based on millepachine. Biological evaluation revealed compound 5h exhibited significant antiproliferative activity against osteosarcoma cell U2OS and MG-63. And compound 5h also remarkably inhibited tubulin polymerization. Further investigations indicated compound 5h not only arrest U2OS cells cycle at the G2/M phases, but also induced U2OS cells Apoptosis in dose-dependent manners. Moreover, compound 5h was verified to inhibit cell migration and angiogenesis of HUVECs, induce mitochondrial membrane potential decreased and promoted the elevation of ROS levels. Furthermore, compound 5h exhibited remarkable effects on tumor growth in vivo, and the TGI rate was up to 84.94 % at a dose of 20 mg/kg without obvious toxicity. These results indicated that 5h may be an appealing tubulin inhibitor for treatment of osteosarcoma.

Keywords

Antiproliferative activity; Antitumor; Millepachine; Tubulin colchicine binding site.

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