117048-59-6Relevant articles and documents
Combretastatin A-4 inhibits cell growth and metastasis in bladder cancer cells and retards tumour growth in a murine orthotopic bladder tumour model
Shen, Cheng-Huang,Shee, Jia-Jen,Wu, Jin-Yi,Lin, Yi-Wen,Wu, Jiann-Der,Liu, Yi-Wen
, p. 2008 - 2027 (2010)
BACKGROUND AND PURPOSE Bladder cancer is a highly recurrent cancer after intravesical therapy, so new drugs are needed to treat this cancer. Hence, we investigated the anti-cancer activity of combretastatin A-4 (CA-4), an anti-tubulin agent, in human bladder cancer cells and in a murine orthotopic bladder tumour model. EXPERIMENTAL APPROACH Cytotoxicity of CA-4 was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, propidium iodide (PI) staining assay and clonogenic survival assay. In vivo microtubule assembly assay, cell cycle analyses, Western blot and cell migration assay were used to study the mechanism of CA-4. The effect of intravesical CA-4 therapy on the development of tumours was studied in the murine orthotopic bladder tumour model. KEY RESULTS CA-4 inhibited microtubule polymerization in vivo. Cytotoxic IC50 values of CA-4 in human bladder cancer cells were below 4 nM. Analyses of cell-cycle distribution showed CA-4 obviously induced G2-M phase arrest with sub-G1 formation. The analyses of apoptosis showed that CA-4 induced caspase-3 activation and decreased BubR1 and Bub3 in cancer cells. In addition to apoptosis, CA-4 was also found to induce the formation of multinucleated cells. CA-4 had a significantly reduced cell migration in vitro. Importantly, the in vivo study revealed that intravesical CA-4 therapy retarded the development of murine bladder tumours. CONCLUSIONS AND IMPLICATIONS These data demonstrate that CA-4 kills bladder cancer cells by inducing apoptosis and mitotic catastrophe. It inhibited cell migration in vitro and tumour growth in vivo. Hence, CA-4 intravesical therapy could provide another strategy for treating superficial bladder cancers.
Combretastatin A-4 Analogue: A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV) Moiety with a Unique Mode of Action
Huang, Xiaochao,Huang, Rizhen,Gou, Shaohua,Wang, Zhimei,Liao, Zhixin,Wang, Hengshan
, p. 2132 - 2148 (2016)
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.
A protecting group-free synthesis of the antineoplastic agent combretastatin A4
Guo, Xiaotao,Zhang, Dan,Yu, Zhifang,Liu, Tianzhen,Li, Dachang,Li, Chunbao
, p. 229 - 230 (2011)
The synthesis of combretastatin A4 (CA4) from commercially available inexpensive materials has been achieved via the Wittig reaction followed by irradiation of the (Z)/(E)-CA4 reaction mixture with sunlight. The method resulted in (Z)-CA4 in high yield. This method does not require protection of the phenolic hydroxy group. The synthesis is operationally simple and cost-efficient.
Synthesis and in Vitro Bioactivity of Polyunsaturated Fatty Acid Conjugates of Combretastatin A-4
Ojike, Fredrick O.,Lavignac, Nathalie,Casely-Hayford, Maxwell A.
, p. 2101 - 2105 (2018)
Combretastatin A-4 (CA-4) (1) is a plant-derived anticancer agent binding to the tubulin colchicine site. Polyunsaturated fatty acids (PUFAs) are readily taken up by cancer cells and have been used to improve cell targeting. In the present study, four CA-4-PUFA conjugates were synthesized by coupling combretastatin A-4 (1) with several polyunsaturated fatty acids. The conjugates (2a-d) were characterized using spectroscopic methods. Their cytotoxicity was evaluated against human breast cancer cells (MCF-7), and the inhibition of tubulin polymerization was determined in vitro. All conjugates influenced tubulin polymerization, with the arachidonic acid conjugate (2c) displaying cytotoxicity similar in potency to the natural product CA-4 (1).
Synthesis and Cytotoxicity Studies of Stilbene Long-Chain Fatty Acid Conjugates
Brown, David P.,Chen, Zhe-Sheng,Narayanan, Silpa,Wong, Thomas
, (2020)
A series of 16 conjugates of the tubulin polymerization inhibitor combretastatin A4 (CA-4) and other functionally related stilbene with four 18-carbon fatty acids, namely, stearic, oleic, linoleic, and linolenic acids, have been synthesized in good yields. These new derivatives have been evaluated against the KB-3-1 (human epidermoid carcinoma), NCI-H460 (human lung cancer), HEK293 (human embryonic kidney), and MCF-7 (human breast adenocarcinoma) cell lines for antiproliferative activity, with the exhibited cytotoxic activities comparable with those of CA-4 and colchicine. Compounds 22 and 23, CA-4 conjugates of linoleic and linolenic acids, respectively, were determined to have exhibited the most active in vitro assays, with compound 23 exhibiting very similar activity to the parent compound against the NCI-H460 cell line. Our studies further delineated the structurally required Z-geometry of the stilbene moiety and that conjugation of the less active E-stilbenes with the most active fatty acid had minimal or no improvement in their respective activities.
Design, synthesis and biological evaluation of combretastatin A-4 sulfamate derivatives as potential anti-cancer agents
Huang, Jinwen,Huang, Leilei,Li, Yingzi,Nie, Hui,Song, Lixing,Wu, Fanhong
supporting information, p. 1374 - 1380 (2021/09/30)
A series of combretastatin A-4 (CA-4) sulfamate derivatives were synthesized and their structure-activity relationship on tubulin, arylsulfatase and tumor cell antiproliferation inhibition was studied. Among them, compound 16a showed excellent potency as well as CA-4 under the same conditions against six tumor cells including HTC-116, HeLa, HepG2, MGC803, MKN45 and MCF-7 cells, respectively. Molecular docking revealed that several important hydrogen bond interactions were formed between the sulfamate group of 16a and the colchicine binding site of tubulin and steroid sulfatase respectively. Although compound 16a was less active than CA-4 in regard to its in vitro activity as an inhibitor of tubulin polymerization, it was effective as an inhibitor of arylsulfatase. This novel combretastatin A-4 sulfamate derivative has the potential to be developed as a dual inhibitor of tubulin polymerization and arylsulfatase for cancer therapy.
An Amine-Assisted Ionic Monohydride Mechanism Enables Selective Alkyne cis-Semihydrogenation with Ethanol: From Elementary Steps to Catalysis
Huang, Zhidao,Wang, Yulei,Leng, Xuebing,Huang, Zheng
supporting information, p. 4824 - 4836 (2021/04/07)
The selective synthesis of Z-alkenes in alkyne semihydrogenation relies on the reactivity difference of the catalysts toward the starting materials and the products. Here we report Z-selective semihydrogenation of alkynes with ethanol via a coordination-induced ionic monohydride mechanism. The EtOH-coordination-driven Cl- dissociation in a pincer Ir(III) hydridochloride complex (NCP)IrHCl (1) forms a cationic monohydride, [(NCP)IrH(EtOH)]+Cl-, that reacts selectively with alkynes over the corresponding Z-alkenes, thereby overcoming competing thermodynamically dominant alkene Z-E isomerization and overreduction. The challenge for establishing a catalytic cycle, however, lies in the alcoholysis step; the reaction of the alkyne insertion product (NCP)IrCl(vinyl) with EtOH does occur, but very slowly. Surprisingly, the alcoholysis does not proceed via direct protonolysis of the Ir-C(vinyl) bond. Instead, mechanistic data are consistent with an anion-involved alcoholysis pathway involving ionization of (NCP)IrCl(vinyl) via EtOH-for-Cl substitution and reversible protonation of Cl- ion with an Ir(III)-bound EtOH, followed by β-H elimination of the ethoxy ligand and C(vinyl)-H reductive elimination. The use of an amine is key to the monohydride mechanism by promoting the alcoholysis. The 1-amine-EtOH catalytic system exhibits an unprecedented level of substrate scope, generality, and compatibility, as demonstrated by Z-selective reduction of all alkyne classes, including challenging enynes and complex polyfunctionalized molecules. Comparison with a cationic monohydride complex bearing a noncoordinating BArF- ion elucidates the beneficial role of the Cl- ion in controlling the stereoselectivity, and comparison between 1-amine-EtOH and 1-NaOtBu-EtOH underscores the fact that this base variable, albeit in catalytic amounts, leads to different mechanisms and consequently different stereoselectivity.
