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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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DOI: 10.4236/ojmc.2015.51002    4,112 Downloads   4,654 Views   Citations

ABSTRACT

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 C-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.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Fortin, S. , Wei, L. , Kotra, L. and C.-Gaudreault, R. (2015) 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?. Open Journal of Medicinal Chemistry, 5, 9-22. doi: 10.4236/ojmc.2015.51002.

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