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Mechanistic insights into the activation of ester prodrugs of 666-15.

ABSTRACT: cAMP-response element binding protein (CREB) is an oncogenic transcription factor implicated in many different types of cancer. We previously reported the discovery of 666-15 as a potent inhibitor of CREB-mediated gene transcription. In an effort to improve the aqueous solubility of 666-15, amino ester prodrugs 1 and 4 were designed and synthesized. Detailed chemical and biological studies of 1 and 4 revealed that a small portion of the prodrugs were converted into 666-15 through intermediate 3 instead of a long-range O,N-acyl transfer reaction that was initially proposed. These results provide unique insights into the activation of these ester prodrugs.

SUBMITTER: Xie F

PROVIDER: S-EPMC7530057 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Mechanistic insights into the activation of ester prodrugs of 666-15.

Xie Fuchun F Martín-Acosta Pedro P Li Bingbing X BX Xiao Xiangshu X

Bioorganic & medicinal chemistry letters 20200728 19

cAMP-response element binding protein (CREB) is an oncogenic transcription factor implicated in many different types of cancer. We previously reported the discovery of 666-15 as a potent inhibitor of CREB-mediated gene transcription. In an effort to improve the aqueous solubility of 666-15, amino ester prodrugs 1 and 4 were designed and synthesized. Detailed chemical and biological studies of 1 and 4 revealed that a small portion of the prodrugs were converted into 666-15 through intermediate 3 ...[more]

PMID: 32730943

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