N-Phenyl-N′-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. Part 3: Role of carbonyl groups in the covalent binding to the colchicine-binding site

Moreau, Emmanuel; Fortin, Sébastien; Lacroix, Jean-Michel; Patenaude, Alexandre; Rousseau, Jean L.C.; C-Gaudreault, René

doi:10.1016/j.bmc.2007.10.078

Cited by 16 publications

(22 citation statements)

References 26 publications

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“…This adduct is easily detectable by Western blot as a second immunoreacting band of β-tubulin [16,21,[26][27][28][29]. As seen in Figure These results also show that that the TMP moiety is not essential for the affinity and the acylation of the C-BS.…”

Section: Sceus Acylate the Glutamic Acid Residue In Position 198 Of Tsupporting

confidence: 65%

Styryl-N-phenyl-N′-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model

Gagné-Boulet

Fortin

Lacroix

et al. 2015

European Journal of Medicinal Chemistry

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Combretastatin A-4 (CA-4) is a well-studied and attractive molecular template to develop new antimitotics. Several thousand of modifications were performed on the ring B and the ethenyl bridge of CA-4 but only a few involved the trimethoxyphenyl moiety (TMP, ring A) often considered essential to the antiproliferative and antimicrotubule activities. In this study, we described the design, the preparation, the characterization and the biological evaluation of three new series of CA-4 analogs namely styryl-N-phenyl-N'-ethylureas (SEUs), styryl-N-phenyl-N'-(2-chloroethyl)ureas (SCEUs) and styrylphenylimidazolidin-2-ones (SIMZs) bearing a 3-Cl (series a), 3,5-Me (series b) and TMP (series c) substituents, respectively. All SCEU and SIMZ Z-isomers were active in the high and the low nanomolar range, respectively. Conversely to SEUs and their E-isomers that were significantly less active or inactive. Interestingly, the TMP moiety is giving rise to derivatives exhibiting the lowest antiproliferative activity in the SCEU series (10c) and the most active compound in the SIMZ series (12c). Moreover, SIMZ Z-isomers bearing either a 3-Cl (12a) or a 3,5-Me (12b) exhibited antiproliferative activities that are also in the same order of magnitude as 12c. All SCEU and SIMZ Z-isomers also arrested the cell cycle progression in G2/M phase, bound to the colchicine-binding site and disrupted the cytoskeleton of cancer cells. In addition to the promising and innovative microtubule-disrupting properties of SCEUs and SIMZs, these results show that the TMP moiety is not essential for the cytocidal activity of these new CA-4 analogs.

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Section: Sceus Acylate the Glutamic Acid Residue In Position 198 Of Tsupporting

confidence: 65%

Styryl-N-phenyl-N′-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model

Gagné-Boulet

Fortin

Lacroix

et al. 2015

European Journal of Medicinal Chemistry

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“…The acylation of Glu198 leads to microtubule depolymerization, hypoacetylation of Lys40 on α-tubulin, cytoskeleton disruption, and anoikis. 24,25 CEU analogues such as 1-(2-chloroethyl)-3-(4-iodophenyl)urea ( 5 ) 26−28 or 1-(2-chloroethyl)-3-(3-(5-hydroxypentyl)phenyl)urea ( 6 ) 29−31 inhibit angiogenesis and tumor growth in three distinct animal models. (25) The biodistribution of CEU analogues to organs of the gastrointestinal tract suggests that they might be promising new drugs for the treatment of colorectal cancers.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

et al. 2011

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Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G2/M phase and bind to the colchicine-binding site on β-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure–activity relationships.

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“…Previous SAR studies in our laboratory have demonstrated that both N-phenyl-N'-(2-chloroethyl)ureas (5a-5d) and their phenyl 2-aminoxazoline (6a, 6b) bioisosteric equivalents (Figure 1) could replace the 3,4,5-trimethoxyphenyl moiety (ring A) of CA-4 and bind to the C-BS with similar spatial conformations [34]- [42]. To further assess the potential of the N-phenyl-N'-(2-chloroethyl)urea moiety for the development of new VDAs derived from CA-4, we develop analogues with low-molecular weight derived from substituted phenyl 4-(2- oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs, 9-67) [43] and phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides (PIB-SAs, A8-A48) [44], where the 2-chloroethylurea moiety is cyclized under basic conditions into the corresponding 2-imidazolidone ring.…”

Section: Introductionmentioning

confidence: 97%

“…PIB-SOs and PIB-SAs exhibit antiproliferative activities at the nanomolar level towards several tumor cell lines, bind to the C-BS, block cell cycle progression in G2-M phase, disrupt the cytoskeleton and show potent antineoplastic activity towards human fibrosarcoma (HT-1080) tumors grafted onto the chorioallantoic membrane of developing chicks, and low systemic toxicity towards the embryos [43] [44]. Based on SAR studies of N-phenyl-N'-(2-chloroethyl)ureas [34]- [42], we hypothesize that the phenyl 2-imidazolidinone moiety of PIB-SOs and PIB-SAs might also mimic the 3,4,5-trimethoxyphenylated ring A of CA-4 and could be used as a bioisosteric equivalent for the development of new VDAs derived from CA-4.…”

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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N-Phenyl-N′-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. Part 3: Role of carbonyl groups in the covalent binding to the colchicine-binding site

Cited by 16 publications

References 26 publications

Styryl-N-phenyl-N′-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model

Styryl-N-phenyl-N′-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model

Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

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?

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