Trapping phosphodiester-quinone methide adducts through in situ lactonization |
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Authors: | Zhou Q Turnbull K D |
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Institution: | Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville 72701, USA. |
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Abstract: | The goal of in situ modification of DNA via phosphodiester alkylation has led to our design of quinone methide derivatives capable of alkylating dialkyl phosphates. A series of catechol derivatives were investigated to trap the phosphodiester-quinone methide alkylation adduct through in situ lactonization. The catechol derivatives were uniquely capable of characterizable p-quinone methide formation for mechanistic clarity. These investigations revealed that with a highly reactive lactonization group (phenyl ester), lactonization competed with quinone methide formation. Lactone-forming groups of lower reactivity (methyl ester, n-propyl ester, and dimethyl amide) allowed quinone methide formation followed by phosphodiester alkylation; however, they were ineffective at in situ lactonization to drain the phosphodiester alkylation equilibrium to the desired phosphotriester product. The derivatives tethered with lactone-forming functionality of intermediate reactivity (chloro-, trichloro-, and trifluoroethyl esters), allowed quinone methide formation, phosphodiester alkylation, and in situ lactonization to efficiently afford the trapped phosphotriester adduct. |
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