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.

Design, Synthesis and Biological Evaluation of Prodrugs of 666-15 as Inhibitors of CREB-Mediated Gene Transcription

“…We attribute the instability of these esters to the formation of imide structure 8 that can be easily degraded or rearranged into other products through cleavage of the imide. This is consistent with what we observed with other esters of this type …”

“…24,25 While we observed significant increase of the aqueous solubility of the resulting amino esters, the expected long-range O,N-acyl transfer reaction was not efficient, resulting in low conversion into 666-15. 25 In this paper, we describe the development of novel prodrugs of 666-15 with efficient release of 666-15 and improved in vivo pharmacokinetic (PK) properties.…”

“…One limitation of 666-15 is that its aqueous solubility is not optimal (<100 μM in PBS by turbidity assay to be measured by absorbance at 620 nm), which might limit its in vivo oral bioavailability. Recently, we introduced “traceless” prodrugs of 666-15 by designing its corresponding amino esters through a long-range O , N -acyl transfer reaction to increase its aqueous solubility. , While we observed significant increase of the aqueous solubility of the resulting amino esters, the expected long-range O , N -acyl transfer reaction was not efficient, resulting in low conversion into 666-15 . In this paper, we describe the development of novel prodrugs of 666-15 with efficient release of 666-15 and improved in vivo pharmacokinetic (PK) properties.…”

“…Compound 1 was designed by appending an additional free amino group using amino acids to make the corresponding esters. It is anticipated that the addition of an additional ionizable amino group will significantly boost its aqueous solubility and perhaps oral bioavailability. ,, Sulfate 2 and phosphates 3 and 4 were designed to be activatable by sulfatases and phosphatases in circulation, respectively. The synthesis of compound 1 is presented in Scheme .…”

Targeting CREB in Cancer Therapy: A Key Candidate or One of Many? An Update

“…Although non-cancer beneficial therapeutic effects have also been described for 666-15, such as prevention of ROS-induced cardiac hypertrophy, serious cellular damage has been reported specifically against central nervous system [124][125][126]. In the effort of improving both solubility and bioavailability, a novel ester prodrug of 666-15 was recently identified by Xie and coworkers [127].…”