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

Bioorg Med Chem Lett. 2020 Oct 1;30(19):127455. doi: 10.1016/j.bmcl.2020.127455. Epub 2020 Jul 28.

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.

Keywords: CREB; Cancer; Inhibitor; Prodrug; Transcription.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anilides / chemical synthesis
  • Anilides / metabolism
  • Anilides / pharmacology*
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors*
  • Drug Stability
  • Esters / chemical synthesis
  • Esters / metabolism
  • Esters / pharmacology*
  • HEK293 Cells
  • Humans
  • Hydrolysis
  • Naphthalenes / chemical synthesis
  • Naphthalenes / metabolism
  • Naphthalenes / pharmacology*
  • Prodrugs / chemical synthesis
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Solubility

Substances

  • 666-15 compound
  • Anilides
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Esters
  • Naphthalenes
  • Prodrugs