Combretastatin-like chalcones as inhibitors of microtubule polymerisation. Part 2: Structure-based discovery of alpha-aryl chalcones

Ducki, Sylvie; Mackenzie, Grant; Greedy, Ben; Armitage, Simon; Chabert, Jérémie Fournier Dit; Bennett, Elizabeth; Nettles, Jim; Snyder, James P.; Lawrence, Nicholas J.

doi:10.1016/j.bmc.2009.09.044

Cited by 75 publications

(48 citation statements)

References 27 publications

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“…Boumendjel et al [24] similarly synthesized a library of chalcones and identified 3 candidates demonstrating significant antimitotic activity, again with IC 50 s in the low micromolar range. As demonstrated by Ducki et al , antimitotic activity appeared to be highly correlated to the degree of methoxylation (25, 26). These candidates were further tested in vivo and found to be nontoxic in animal models.…”

Section: Chalcones Target Tubulin Polymerizationmentioning

confidence: 80%

“…Ducki et al [25, 26] presented a thorough review of alpha-aryl chalcone derivatives, whose structure-activity relationship studies demonstrated both antimitotic properties (IC 50 s in the low micromolar range) in K562 leukemia cells with arrest at G2/M phase, as well as antivascular activity (discussed below, see Angiogenesis ). Boumendjel et al [24] similarly synthesized a library of chalcones and identified 3 candidates demonstrating significant antimitotic activity, again with IC 50 s in the low micromolar range.…”

Section: Chalcones Target Tubulin Polymerizationmentioning

confidence: 99%

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Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

Jandial¹,

Blair²,

Zhang³

et al. 2014

CCDT

114

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There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy.

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Section: Chalcones Target Tubulin Polymerizationmentioning

confidence: 80%

Section: Chalcones Target Tubulin Polymerizationmentioning

confidence: 99%

Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

Jandial¹,

Blair²,

Zhang³

et al. 2014

CCDT

114

View full text Add to dashboard Cite

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“…Thus, most modifications of combretastatins have been directed to ring B and the ethenyl bridge. Modifications of ring B have included, but have not been limited to, different substitutions on the phenyl, heteroaromatic or heterocyclic rings [21]- [24], and the unstable ethenyl bridge is substituted either with sulfonate ( Figure 1) [25] [26], chalcone [27] [28], imidazole [29], triazole [30] [31], furazan [32], pyrazole or 1,3-thiazole [33] derivatives.…”

Section: Introductionmentioning

confidence: 99%

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

Fortin¹,

Wei²,

Kotra³

et al. 2015

OJMC

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Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the * Corresponding author. S. Fortin et al. 10C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, respectively.

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“…17) CA-4 phosphate (Zybrestat) is a water soluble prodrug that is currently in phase III clinical trials. [18][19][20] One of the strategies to prevent in vivo cis/trans isomerization associated with the inactivation of CA-4 was the replacement of the olefinic bridge in CA-4 with an appropriate heterocyclic ring aiming to rigidify the structure and restrict its rotation. 21,22) In the present study, the design of the new compounds was based upon the potent cytotoxic activity displayed by the oxadiazoline derivative A-105972 that interacts with the microtubules and induces apoptosis.…”

mentioning

confidence: 99%

Synthesis of New <i>N</i><sup>1</sup>-Substituted-5-aryl-3-(3,4,5-trimethoxyphenyl)-2-pyrazoline Derivatives as Antitumor Agents Targeting the Colchicine Site on Tubulin

Elmeligie

Khalil

Ahmed

et al. 2016

Biological & Pharmaceutical Bulletin

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A series of pyrazoline derivatives 2a-e, 3a-e and 4a-e structurally related to combretastatin A4 (CA-4) were synthesized and characterized by spectroscopic means and elemental analyses. In these compounds, the cis double bond of CA-4 was replaced with the pyrazoline ring aiming to enhance the cytotoxic effects displayed by CA-4 and to prevent the cis/trans isomerization that is associated with inactivation of CA-4. The cytotoxic activity of all new compounds was investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by the most active compounds 3d, 4a and e was evaluated. The cytotoxicity of 4e was correlated with induction of apoptosis and caspase-3 activation in vitro thus indicating the apoptotic pathway of anticancer effect of these compounds. Furthermore, in vivo evaluation of the synthesized compounds was carried out against Ehrlich's ascites carcinoma (EAC) solid tumor grown in mice. Compounds 2c, 3a and e showed significant reduction in tumor weight, and about 2-4 fold increase in caspase-3 expression.

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Combretastatin-like chalcones as inhibitors of microtubule polymerisation. Part 2: Structure-based discovery of alpha-aryl chalcones

Cited by 75 publications

References 27 publications

Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

Molecular Targeted Approaches to Cancer Therapy and Prevention Using Chalcones

Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?

Synthesis of New <i>N</i><sup>1</sup>-Substituted-5-aryl-3-(3,4,5-trimethoxyphenyl)-2-pyrazoline Derivatives as Antitumor Agents Targeting the Colchicine Site on Tubulin

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