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.
Highlights
Cancer has recently become the leading cause of death in North America [1] [2] and worldwide [3]
Based on structure-activity relationship (SAR) studies of N-phenyl-N’-(2-chloroethyl)ureas [34]-[42], we hypothesize that the phenyl 2-imidazolidinone moiety of Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin1-yl)benzenesulfonamides (PIB-SAs) might mimic the 3,4,5-trimethoxyphenylated ring A of combretastatin A-4 (CA-4) and could be used as a bioisosteric equivalent for the development of new Vascular disrupting agents (VDAs) derived from CA-4
We have investigated the key interacting elements of PIB-SOs and PIB-SAs and their spatial conformation within the colchicine-binding site (C-BS) in order to confirm that the novel phenyl 2-imidazolidinone moiety of PIB-SOs and PIB-SAs can be used as a bioisosteric equivalent of the 3,4,5-trimethoxyphenyl haptophore of CA-4 for the design of new, potent antimitotics
Summary
Cancer has recently become the leading cause of death in North America [1] [2] and worldwide [3]. 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]. 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 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. We disclose the common binding sites and potential correlations with the factors for the antiproliferative activities using the spatial conformations of PIB-SOs and PIB-SAs as well as other inhibitors of the C-BS including CA-4 (1), T138067 (3), ABT-751 (4), colchicine (7) and TN-16 (8). Our computational modeling results will be beneficial for the design of novel antimicrotubule agents targeting the C-BS
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
