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

Jiangling Peng, Mark Miller, Bingbing X. Li, Xiangshu Xiao

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)388-395
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume13
Issue number3
DOIs
StatePublished - Mar 10 2022
Externally publishedYes

Keywords

  • 666-15
  • CREB
  • Cancer
  • Inhibitor
  • Oral bioavailability
  • Prodrug

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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