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.
Dual-targeting antitumor conjugates derived from platinum(IV) prodrugs and microtubule inhibitor CA-4 significantly exhibited potent ability to overcome cisplatin resistance
Huang, Xiaochao,Wang, Meng,Wang, Chungu,Hu, Weiwei,You, Qinghong,Yang, Yong,Yu, Chunhao,Liao, Zhixin,Gou, Shaohua,Wang, Hengshan
, (2019)
Here we report that three platinum(IV) prodrugs containing a tubulin inhibitor CA-4, as dual-targeting platinum(IV) prodrug, were synthesized and evaluated for antitumor activity using MTT assay. Among them, complex 9 exhibited the most potent antitumor activity against the tested cancer lines including cisplatin resistance cancer cells, and simultaneously displayed lower toxicity compared to cisplatin, respectively. Moreover, complex 9, in which was conjugated to an inhibitor of tubulin at one axial position of platinum(IV) complex, could effectively enter the cancer cells, and significantly induce cell apoptosis and arrest the cell cycle in A549 cells at G2/M stage, and dramatically disrupt the microtubule organization. In addition, mechanism studies suggested that complex 9 significantly induced reactive oxygen species (ROS) generation and decreased mitochondrial trans-membrane potential (MMP) in A549 cells, and effectively induced activation of caspases triggering apoptotic signaling through mitochondrial dependent apoptosis pathways.
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.
New efficient synthesis of combretastatin A-4 via Colvin rearrangement
Petrov, Ognyan I.,Gerova, Mariana S.,Chanev, Christo D.,Petrova, Katya V.
, p. 3711 - 3715 (2011)
A new four-step approach for the synthesis of anticancer agent combretastatin A-4 (CA-4) has been developed. The method includes the Colvin rearrangement of the benzophenone derivative phenstatin to the key diarylalkyne followed by stereoselective semi-reduction to CA-4 in good overall yield.
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.
Design, Synthesis, and in vitro and in vivo Evaluations of (Z)-3,4,5-Trimethoxystyrylbenzenesulfonamides/sulfonates as Highly Potent Tubulin Polymerization Inhibitors
Mahesh, Rasala,Nayak, Vadithe Lakshma,Babu, Korrapati Suresh,Riyaz, Syed,Shaik, Thokhir Basha,Kumar, Gajjela Bharth,Mallipeddi, Prema Latha,Reddy, Challa Ratna,Shekar, Kunta Chandra,Jose, Jedy,Nagesh, Narayana,Kamal, Ahmed
, p. 678 - 700 (2017)
Newer therapeutics can be developed in drug discovery by adopting the strategy of scaffold hopping of the privileged scaffolds from known bioactive compounds. This strategy has been widely employed in drug-discovery processes. Structure-based docking studies illustrate the basic underlying concepts and reveal that interactions of the sulfonamide group and hydrophobic interactions are crucial. On the basis of this strategy, over 60 synthetic analogues were synthesized and evaluated for their cytotoxicity against the NCI panel of 60 human cancer cell lines; the majority of these compounds exhibited promising cytotoxicity with GI50 values ranging between 18 and 50 nm. Among these compounds, (Z)-N-[2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (7 a) and (Z)-N-[2-hydroxy-3-methoxy-6-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (9 a) were found to be potent. Similar results were obtained against three human cancer cell lines with IC50 values ranging between 0.04 and 3.0 μm. Studies aimed at elucidating the mechanism of action of these new analogues revealed that they inhibited the in vitro polymerization of tubulin and disorganized the assembly of microtubules in HeLa and MCF-7cancer cells. Lead compounds 7 a and 9 a displayed notable in vivo antitumor activity in a HeLa tumor xenograft model. Our studies have resulted in the identification of a scaffold that can target tubulin polymerization, which should have significant potential toward the development of new antitumor drugs.
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).
The synthesis of (E) and (Z)-combretastatins A-4 and a phenanthrene from Combretum caffrum
Lawrence, Nicholas J.,Ghani, Fazni Abdul,Hepworth, Lucy A.,Hadfield, John A.,McGown, Alan T.,Pritchard, Robin G.
, p. 1656 - 1660 (1999)
The synthesis of the trans stilbene E-combretastatin A-4 has been achieved via a Horner-Wittig reaction of (3,4,5- trimethoxybenzyl)diphenylphosphine oxide. The anticancer drug Z- combretastatin A-4 was prepared by the hydroboration/protonation of a diaryl- alkyne.
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.
Heterobimetallic Pd/Mn and Pd/Co complexes as efficient and stereoselective catalysts for sequential Cu-free Sonogashira coupling–alkyne semi-hydrogenation reactions
Baweja, Saral,Clauss, Reike,Gelman, Dmitri,Hey-Hawkins, Evamarie
, p. 1344 - 1356 (2022/02/03)
A series of heterobimetallic PdII/MII complexes (MII = Mn, Co) were synthesised and tested as precatalysts for sequential Sonogashira coupling–alkyne semi-hydrogenation reactions to form Z-aryl alkenes. The carbometalated heterobimetallic PdII/CoII complex CoPdL3′ demonstrated an apparent cooperative effect compared to the corresponding monometallic counterparts. This compound was identified as a potent single-molecule catalyst for the one-pot Cu-free Sonogashira coupling of aryl bromides with terminal alkynes followed by chemo- and stereoselective semi-hydrogenation of the alkyne intermediate using NH3·BH3 as a hydrogen source. Furthermore, different aromatic substrates have been tested to show the generality of the reaction for the synthesis of Z-alkenes, including biologically active combretastatin A-4. In addition, the homogeneous nature of the catalytically active species was demonstrated.
