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. 2015 Mar 1;25(5):1044-6.
doi: 10.1016/j.bmcl.2015.01.020. Epub 2015 Jan 20.

Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP

Tyler D Baguley  1 , Angus C Nairn  2 , Paul J Lombroso  3 , Jonathan A Ellman  4
Affiliations

Synthesis of benzopentathiepin analogs and their evaluation as inhibitors of the phosphatase STEP

Tyler D Baguley et al. Bioorg Med Chem Lett. .

Abstract

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain specific protein tyrosine phosphatase that has been implicated in many neurodegenerative diseases, such as Alzheimer's disease. We recently reported the benzopentathiepin TC-2153 as a potent inhibitor of STEP in vitro, cells and animals. Herein, we report the synthesis and evaluation of TC-2153 analogs in order to define what structural features are important for inhibition and to identify positions tolerant of substitution for further study. The trifluoromethyl substitution is beneficial for inhibitor potency, and the amine is tolerant of acylation, and thus provides a convenient handle for introducing additional functionality such as reporter groups.

Keywords: Alzheimer’s disease; Inhibitor; Phosphatase; Redox; STEP.

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Figures

Figure 1
Figure 1
Proposed SAR study of TC-2153.
Scheme 1
Scheme 1
Original synthesis of benzopentathiepin compoundsa aReagents and conditions: (a) sodium dimethyldithiocarbamate, DMSO, rt or 150 °C; (b) NaSH, DMSO, rt.
Scheme 2
Scheme 2
Synthesis of less electron deficient analogs 18 and 19a aReagents and conditions: (a) NH4Cl, Zn0, EtOH, H2O, rt; (b) SnCl2, HCl, H2O, EtOH, 40 °C; (c) NaSH, DMSO, rt; (d) HCl, ether, rt.
Scheme 3
Scheme 3
Synthesis of TC-2153 analog 22a aReagents and conditions: (a) sodium dimethyldithiocarbamate, DMSO, 200 °C; (b) NaSH, DMSO, rt.
Scheme 4
Scheme 4
Synthesis of TC-2153 analogs 23 and 24a aReagents and conditions: (a) AcCl or TFAA, CH2Cl2, °C to rt.
Scheme 5
Scheme 5
Synthesis of TC-2153 analogs 25 and 26a aReagents and conditions: (a) RCHO, AcOH, EtOH, 0 °C; (b) NaCNBH3, 0 °C
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