4-(3-Halo/amino-4,5-dimethoxyphenyl)-5-aryloxazoles and -<i>N</i>-methylimidazoles That Are Cytotoxic against Combretastatin A Resistant Tumor Cells and Vascular Disrupting in a Cisplatin Resistant Germ Cell Tumor Model

Schobert, Rainer; Biersack, Bernhard; Dietrich, Andrea M.; Effenberger, Katharina E.; Knauer, Sebastian; Mueller, Thomas

doi:10.1021/jm100345r

Cited by 80 publications

(40 citation statements)

References 22 publications

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“…The rationale of the design of active compounds was to retain the appropriate geometry of the two adjacent aryl groups required for potent bioactivity of chemically stable cis-restricted derivatives of CA-4. These were obtained by incorporating the olefinic double bond into vicinally diaryl-substituted fivemember aromatic heterocyclic rings (Table 1), such as pyrazole [67], imidazole [67][68][69], thiazole [70][71][72], furazan (1,2,5-oxadiazole) [73], furan [74,75], thiophene [76,77], isoxazole [78,79], oxazole [67,68,80,81], 1,2,3-thiadiazole [39], triazole [82,83,84,85], 1,2,3,4-tetrazole [70,86] and dioxolane [87]. Replacement of the olefinic bond with a five-member heterocyclic ring allowed the retention of the correct geometric orientation of the two phenyl rings of CA-4, placing them at an appropriate distance for efficient interaction with the colchicine-binding domain on tubulin [35].…”

Section: Other Synthetic Stilbene Derivatives As Tubulin-interactive mentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

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Section: Other Synthetic Stilbene Derivatives As Tubulin-interactive mentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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“…Regardless of their specificity most of the clinically used HDACi tend to induce resistance in tumour cells [33,34]. As a potential workaround we recently developed a new HDACi motif that links the common 2nd-generation para-cinnamylhydroxamate pharmacophore to 4,5-diphenylimidazoles, derived from the natural vascular-disrupting cis-stilbene combretastatin A-4 [35]. Such conjugates showed pronounced pan-HDAC inhibition exceeding that of vorinostat, but they lacked the tubulin affinity typical of the original imidazoles and of combretastatin A-4 [35][36][37].…”

Section: Introductionmentioning

confidence: 99%

4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

Mahal

Kahlen

Biersack

et al. 2015

Experimental Cell Research

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“…However, the cis-configuration of CA-4 is prone to isomerize to the thermodynamically more stable trans-form during storage and metabolism, resulting in a dramatic decrease in its activity [7]. Thus, to retain the appropriate geometry of the two adjacent aryl groups required for a potent bioactivity, chemically stable cis-restricted derivatives of CA-4 were obtained by incorporating the olefinic double bond with vicinal diarylsubstituted five-member aromatic heterocyclic rings, such as pyrazole [8], imidazole [9], thiazole [10], furazan (1,2,5-oxadiazole) [11], isoxazole [12], oxazole [8], 1,2,3-thiadiazole [13], triazole [14] and 1,2,3,4-tetrazole [10]. We recently synthesized [15] a new series of 2-amino-4-(3 0 ,4 0 ,5 0 -trimethoxyphenyl)-5-aryl thiazoles in which we identified compound TR-644 as the most active compound (Fig.…”

Section: Introductionmentioning

confidence: 99%

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

et al. 2013

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TR-644 is a novel combretastatin A-4 (CA-4) analogue endowed with potent microtubule depolymerizing activity superior to that of the lead compound and it also has high affinity to colchicines binding site of tubulin. We tested TR-644 anti-angiogenic effects in human umbilical endothelial cells (HUVEC). It showed no significant effects on the growth of HUVEC cells at concentrations below 1,000 nM, but at much lower concentrations (10-100 nM) it induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the disruption of the microtubule network. TR-644 also increased permeability of HUVEC cells in a time dependent manner. The molecular mechanism for the anti-vascular activity of TR-644 was investigated in detail. TR-644 caused G2/M arrest in endothelial cells and this effect correlated with downregulation of the expression of Cdc25C and Cdc2Tyr15 .Moreover TR-644 inhibited VEGF-induced phosphorylation of VE-cadherin but did not prevent the VEGF-induced phosphorylation of FAK. In chick chorioallantoic membrane in vivo assay, TR-644 (0.1-1.0 pmol/egg) efficiently counteracted the strong angiogenic response induced by FGF. Also CA-4, used as reference compound, caused an antagonistic effect, but in contrast, it induced per se, a remarkable angiogenic response probably due to an inflammatory reaction in the site of treatment. In a mice allogenic tumor model, immunohistochemical staining of tumors with anti-CD31 antibody showed that TR-644 significantly reduced the number of vessel, after 24 h from the administration of a single dose (30 mg/Kg).

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4-(3-Halo/amino-4,5-dimethoxyphenyl)-5-aryloxazoles and -N-methylimidazoles That Are Cytotoxic against Combretastatin A Resistant Tumor Cells and Vascular Disrupting in a Cisplatin Resistant Germ Cell Tumor Model

Cited by 80 publications

References 22 publications

Tubulin-interactive stilbene derivatives as anticancer agents

Tubulin-interactive stilbene derivatives as anticancer agents

4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

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