Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription

Abstract

cAMP-response element binding protein (CREB) is a nuclear transcription factor that has been implicated in the pathogenesis and maintenance of various types of human cancers. Identification of small molecule inhibitors of CREB-mediated gene transcription has been pursued as a novel strategy for developing cancer therapeutics. We recently discovered a potent and cell-permeable CREB inhibitor called 666-15. 666-15 is a bisnaphthamide and has been shown to possess efficacious anti-breast cancer activity without toxicity in vivo. In this study, we designed and synthesized a series of analogs of 666-15 to probe the importance of regiochemistry in naphthalene ring B. Biological evaluations of these analogs demonstrated that the substitution pattern of the alkoxy and carboxamide in naphthalene ring B is very critical for maintaining potent CREB inhibition activity, suggesting that the unique bioactive conformation accessible in 666-15 is critically important.

Keywords: 666-15; Bioactive conformation; CREB; Cancer; Regioisomer.

Figure 1

Chemical structure of 666-15.

Figure 2

Designed regioisomers 1a–1d by changing the substitution pattern on naphthalene ring B of 666-15.

Figure 3

Global conformational energy minima of 666-15 (A), 1a (B), 1b (C), 1c (D) and 1d (E). The yellow dotted line indicates a hydrogen bond and the corresponding interatomic distance is shown in Å. In panel (F), the conformations of 1a–1d are superimposed onto that of 666-15.

Scheme 1

Synthesis of building blocks 4a–4d.

Scheme 2

Synthesis of regioisomers 1a–1d.