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

cAMP-response element binding protein (CREB) is a transcription factor involved in multiple cancers. Chemical inhibitors of CREB represent potential anticancer agents. We previously identified 666-15 as a potent CREB inhibitor. While 666-15 showed efficacious anticancer activity in vivo through intraperitoneal (IP) injection, its oral bioavailability is limited. To increase its oral bioavailability, we describe synthesis and evaluation of prodrugs based on 666-15 . The amino acid esters were attempted, but they were not stable for detailed characterization. The corresponding sulfate and phosphates were prepared. The sulfate of 666-15 was too stable to release 666-15 while the phosphates were converted into 666-15 with half-lives of ∼2 h. Phosphate 3 was also a potent CREB inhibitor with anti-breast cancer activity. Furthermore, compound 3 showed much improved oral bioavailability at 38%. These studies support that 3 can be used as an oral CREB inhibitor while IP administration of 666-15 is preferred for in vivo applications.