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Design and bio-evaluation of novel millepachine derivatives targeting tubulin colchicine binding site for treatment of osteosarcoma.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Oct; Vol. 151, pp. 107624. Date of Electronic Publication: 2024 Jul 09. - Publication Year :
- 2024
-
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.<br />Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Liming Wang reports financial support was provided by Nanjing Medical University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Binding Sites
Structure-Activity Relationship
Molecular Structure
Animals
Bone Neoplasms drug therapy
Bone Neoplasms pathology
Bone Neoplasms metabolism
Cell Line, Tumor
Mice
Cell Movement drug effects
Chalcones
Osteosarcoma drug therapy
Osteosarcoma pathology
Osteosarcoma metabolism
Tubulin metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Tubulin Modulators pharmacology
Tubulin Modulators chemistry
Tubulin Modulators chemical synthesis
Colchicine metabolism
Colchicine chemistry
Colchicine pharmacology
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
Drug Design
Dose-Response Relationship, Drug
Apoptosis drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 151
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39002514
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107624