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. 2012 Apr 26;55(8):4020-4.
doi: 10.1021/jm300043c. Epub 2012 Apr 9.

Design, synthesis, and biological evaluation of conformationally constrained analogues of naphthol AS-E as inhibitors of CREB-mediated gene transcription

Min Jiang  1 , Bingbing X Li, Fuchun Xie, Frances Delaney, Xiangshu Xiao
Affiliations

Design, synthesis, and biological evaluation of conformationally constrained analogues of naphthol AS-E as inhibitors of CREB-mediated gene transcription

Min Jiang et al. J Med Chem. .

Abstract

Cyclic AMP response element binding protein (CREB) is often dysregulated in cancer cells and is an attractive cancer drug _target. Previously, we described naphthol AS-E (1) as a small molecule inhibitor of CREB-mediated gene transcription. To understand its bioactive conformation, a series of conformationally constrained analogues of 1 were designed and synthesized. Biological evaluation of these analogues suggests that the global energy minimum of 1 is the likely bioactive conformation.

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Figures

Figure 1
Figure 1
Potential conformations of compound 1. The yellow dashed lines indicate hydrogen bonds. The dihedral angle of a-b-c-d in 1a is 0.1° while that in 1b is 10.6°.
Figure 2
Figure 2
Molecular electrostatic potential (MEP) surfaces of compounds 1, 4 and 5 mapped to their electron densities calculated at the HF/6-31G** level of theory in Jaguar. The blue indicates electrostatically positively charged while the red is negatively charged. All the surfaces are normalized from −60 to +60 kcal/mol.
Scheme 1
Scheme 1
Synthesis of compound 3.
Scheme 2
Scheme 2
Attempted synthesis of compound 14.
Scheme 3
Scheme 3
Synthesis of compounds 4-6.
Scheme 4
Scheme 4
Synthesis of compound 7.
Chart 1
Chart 1
Structures of designed conformationally constrained compounds 2-7.
See this image and copyright information in PMC

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References

    1. Shaywitz AJ, Greenberg ME. CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68:821–861. - PubMed
    1. Montminy MR, Bilezikjian LM. Binding of a nuclear-protein to the cyclic-AMP response element of the somatostatin gene. Nature. 1987;328:175–178. - PubMed
    1. Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci U S A. 1986;83:6682–6686. - PMC - PubMed
    1. Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989;59:675–680. - PubMed
    1. Radhakrishnan I, PerezAlvarado GC, Parker D, Dyson HJ, Montminy MR, Wright PE. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: A model for activator:Coactivator interactions. Cell. 1997;91:741–752. - PubMed

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