摘要：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.