β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells

Malebari, Azizah M.; Greene, Lisa M.; Nathwani, Seema M.; Fayne, Darren; O’Boyle, Niamh M.; Wang, Shu; Twamley, Brendan; Zisterer, Daniela M.; Meegan, Mary J.

doi:10.1016/j.ejmech.2017.02.049

Cited by 38 publications

(39 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This demonstrates the ability of a thioether substituent to slow or avoid UGT-induced metabolism in this series of compounds, positioning them as lead compounds for resistant colon cancers. These compounds disrupt microtubule structure in both MCF-7 and HT-29 cells by inducing G 2 /M phase arrest and apoptosis [76]. Hence, CA-4's B ring may provide fertile grounds for activity optimization of novel analogues for the treatment of MDR colon cancers.…”

Section: Isoca-4 and Selenium Ca-4 Derivativesmentioning

confidence: 99%

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

2020

Self Cite

View full text Add to dashboard Cite

It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments.

show abstract

Section: Isoca-4 and Selenium Ca-4 Derivativesmentioning

confidence: 99%

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Preparation as described above from crotonyl chloride and (4-methoxybenzylidene)-3,4,5-trimethoxyphenylamine ( 5h ) to afford the product as a brown oil, yield 34% [98]. IR (NaCl) ν max : 1747 (C=O) cm −1 .…”

Section: Methodsmentioning

confidence: 99%

“…Preparation as described above from crotonyl chloride and (4-ethoxybenzylidene)-(3,4,5-trimethoxyphenyl)amine ( 5i ) to afford a colourless solid, yield 33%, Mp 92–93 °C. [98] IR (KBr) ν max : 1749 (C=O) cm −1 . 1 H NMR (400 MHz, CDCl 3 ): δ 1.43 (t, J = 6.84 Hz, 3H), 3.73 (s, 6H), 3.75–3.76 (m, 1H), 3.78 (s, 3H), 4.05 (q, J = 6.86 Hz, 2H), 4.73 (d, J = 2.48 Hz, 1H), 5.33–5.42 (m, 2H), 6.00–6.08 (m, 1H), 6.57 (s, 2H), 6.93 (d, J = 8.80 Hz, 2H), 7.31 (d, J = 8.80 Hz, 2H).…”

Section: Methodsmentioning

confidence: 99%

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

et al. 2019

View full text Add to dashboard Cite

Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 M for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

show abstract

“…20,21 Combretastatin-like compounds bearing an azetidinone unit between the A and B rings were presented by N. M. O'Boyle and colleagues. 22,23 They firstly synthesized a few derivatives of trans 1,3,4 tri-aryl azetidinone 1 (Fig. 2) which inhibited the polymerization of tubulin with a 6-fold rate of inhibition in comparison with the natural compound CA-4.…”

Section: Introductionmentioning

confidence: 99%

“…2) which inhibited the polymerization of tubulin with a 6-fold rate of inhibition in comparison with the natural compound CA-4. 22,23 We recently developed a trans-3-hydroxy-2-azetidinone, bearing in position 1 the A ring and in position 4 the B ring of CA-4 (compound 2) ( Fig. 3).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of new 3-amino-2-azetidinone derivatives as anti-colorectal cancer agents

et al. 2018

View full text Add to dashboard Cite

Several synthetic combretastatin A4 () derivatives were recently prepared to increase the drug efficacy and stability of the natural product isolated from the South African tree . A group of ten 3-amino-2-azetidinone derivatives, as combretastatin A4 analogues, was selected through docking experiments, synthesized and tested for their anti-proliferative activity against the colon cancer SW48 cell line. These molecules, through the formation of amide bonds in position 3, allow the synthesis of various derivatives that can modulate the activity with great resistance to hydrolytic conditions. The cyclization to obtain the 3-aminoazetidinone ring is highly diastereoselective and provides a biologically active isomer under mild reaction conditions with better yields than the 3-hydroxy-2-azetidinone synthesis. All compounds showed IC values ranging between 14.0 and 564.2 nM, and the most active compound showed inhibitory activity against tubulin polymerization , being a potential therapeutic agent against colon cancer.

show abstract

β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells

Cited by 38 publications

References 54 publications

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

Synthesis and biological evaluation of new 3-amino-2-azetidinone derivatives as anti-colorectal cancer agents

Contact Info

Product

Resources

About