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Intramolecular Cyclization of N-phenyl N'(2-chloroethyl)ureas leads to Active N-phenyl-4,5-dihydrooxazol-2-amines Alkylating β-Tubulin Glu198 and Prohibitin Asp40

Abstract : The cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous phenyl '(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEUs subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G/M or G/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, -phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results could be useful for the design of new prodrugs for cancer chemotherapy.
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Anna Trzeciakiewicz, Sébastien Fortin, Emmanuel Moreau, René C. Gaudreault, Jacques Lacroix, et al.. Intramolecular Cyclization of N-phenyl N'(2-chloroethyl)ureas leads to Active N-phenyl-4,5-dihydrooxazol-2-amines Alkylating β-Tubulin Glu198 and Prohibitin Asp40. Biochemical Pharmacology, Elsevier, 2011, 81 (9), pp.1116. ⟨10.1016/j.bcp.2011.02.014⟩. ⟨hal-00685075⟩

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