Combretastatin A‑4 Analogue: A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV) Moiety with a Unique Mode of Action

• Published in: Bioconjugate chemistry Vol. 27; no. 9; pp. 2132 - 2148
• Main Authors: Huang, Xiaochao, Huang, Rizhen, Gou, Shaohua, Wang, Zhimei, Liao, Zhixin, Wang, Hengshan
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.09.2016; Amer Chemical Soc
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bibenzyls - chemistry; Binding sites; Biochemical Research Methods; Biochemistry & Molecular Biology; Biological Transport; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; DNA - metabolism; Drug resistance; Drug Resistance, Neoplasm - drug effects; Humans; Life Sciences & Biomedicine; Membrane Potential, Mitochondrial - drug effects; Models, Molecular; Oncology; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - metabolism; Organoplatinum Compounds - pharmacology; Pharmacology; Physical Sciences; Prodrugs - metabolism; Protein Multimerization - drug effects; Protein Structure, Quaternary; Reactive Oxygen Species - metabolism; Science & Technology; Signal transduction; Statins; Tubulin - chemistry; Tubulin Modulators - chemistry; Tubulin Modulators - metabolism; Tubulin Modulators - pharmacology; APOPTOSIS; DESIGN; POTENT; CISPLATIN; BIOLOGICAL EVALUATION; ANTINEOPLASTIC AGENTS; CELL-CYCLE ARREST; MILLEPACHINE DERIVATIVES; POLYMERIZATION; PLATINUM(IV) COMPLEXES
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.6b00353

Three new Pt­(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt­(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt­(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex 13, which was attached to an inhibitor of tubulin at one axial position of Pt­(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex 13 has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin.