Synthesis and SAR study of N-(4-hydroxy-3-(2-hydroxynaphthalene-1-yl)phenyl)-arylsulfonamides: Heat shock protein 90 (Hsp90) inhibitors with submicromolar activity in an in vitro assay

doi:10.1016/j.bmcl.2008.08.022

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 18, 15 September 2008, Pages 4982-4987

https://doi.org/10.1016/j.bmcl.2008.08.022 Get rights and content

Abstract

Heat shock protein 90 is emerging as an important target in cancer chemotherapy. In a program directed toward identifying novel chemical probes for Hsp90, we found N-(4-hydroxy-3-(2-hydroxynaphthalene-1-yl)phenyl)benzene sulfonamide as an Hsp90 inhibitor with very weak activity. In this report, we present a new and general method for the synthesis of a variety of analogs around this scaffold, and discuss their structure–activity relationships.

Graphical abstract

A versatile synthesis and SAR study of the sulfonamide scaffold are reported.

Section snippets

Acknowledgments

This work was supported by the US National Institutes of Health 1 U54 HG003918-02 and 1R03MH076499-01, and encouraged by Professor Dennis Liotta (Emory University).

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Introduction: Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation. HSP expression is induced by heat shock or other stressors including cellular damage and hypoxia. The major groups, which are classified based on their molecular weight, include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSP (HSP110 and glucose-regulated protein 170). HSPs play a significant role in cellular proliferation, differentiation, survival, apoptosis, and carcinogenesis. The human HSP90 family consists of five members and has a strong association with cancer.
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Results: The HSP90 proteins not only play important roles in cancer development, progression, and metastasis, but also have potential clinical use as biomarkers for cancer diagnosis or assessing disease progression, and as therapeutic targets for cancer therapy. In this chapter, we discuss the roles of HSP90 in cancer biology and pharmacology, focusing on HSP90 as an anti-cancer drug target. An understanding of the functions and molecular mechanisms of HSP90 is critical for enhancing the accuracy of cancer diagnosis as well as for developing more effective and less toxic chemotherapeutic agents.
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Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. The major groups are classified based on their molecular weights and include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. HSPs play a significant role in cellular proliferation, differentiation, and carcinogenesis. In this article we comprehensively review the roles of major HSPs in cancer biology and pharmacology. HSPs are thought to play significant roles in the molecular mechanisms leading to cancer development and metastasis. HSPs may also have potential clinical uses as biomarkers for cancer diagnosis, for assessing disease progression, or as therapeutic targets for cancer therapy.
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Phenyl 3-[(phenylcarbamoyl)amino]benzene-1-sulfonate 26 and phenyl 4-[(phenylcarbamoyl)amino]benzene-1-sulfonate 37 were respectively prepared by coupling sulfonyl chlorides 23 and 34 with methyl 4-hydroxybenzoate in a mixture triethylamine/THF at room temperature [40]. The nitro group of compounds 25–27 and 36–38 was firstly reduced to aniline using a standard catalytic hydrogenation with Pd/C in a mixture of ethyl acetate and ethanol (or methanol) and then hydrolyzed with tBuOK by heating around 40–55 °C to give the desired carboxylic acid derivatives 28–30 and 39–41, respectively [21,41]. To validate and characterize the binding mode of compounds 28–30 and 39–41 with their target protein, we soaked them individually with DENV MTase crystals [17].
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In recent years, considerable attention has been paid to Hsp90 because of its crucial role in the evolution and development of cancer. Hsp90 inhibitors as a significant strategy in cancer therapy include several chemical categories such as isoxazole, pyrimidine, aminoquinolines, arylsulfonamides [15] and pyrazole [16,17]. In this study, a collection of computational procedures were engaged to obtain a new set of compounds that act as dual agents (Hsp90 inhibitor and mutant p53 activator).
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Synthesis and SAR study of N-(4-hydroxy-3-(2-hydroxynaphthalene-1-yl)phenyl)-arylsulfonamides: Heat shock protein 90 (Hsp90) inhibitors with submicromolar activity in an in vitro assay

Abstract

Graphical abstract

Section snippets

Acknowledgments

Drug Discov. Today

J. Biol. Chem.

J. Biol. Chem.

Cell

Bioorg. Med. Chem. Lett.

J. Med. Chem.

Bioorg. Med. Chem. Lett.

Angew. Chem., Int. Ed. Engl.

J. Med. Chem.

Zh. Org. Khim.

Eur. J. Org. Chem.

Tetrahedron Lett.

Phys. Chem. Chem. Phys.

Nat. Rev. Cancer

Bioscience

Cell. Mol. Life Sci.

Proc. Nat. Acad. Sci. U.S.A.