ACS Combinatorial Science
Research Article
assessing enzymatic activity and receptor−ligand binding, re-
spectively. These collaborations have unveiled some interesting
biological activities that have not been previously associated
with the norbenzomorphan class of compounds. Some of these
data obtained from the MLPCN are detailed herein (Table 6).
It is noteworthy that inhibitors of both striatal-enriched
protein tyrosine phosphatase (STEP)16 and fatty acid synthase
(FAS)17 are being investigated as potential therapeutics for the
treatment of Alzheimer’s Disease (AD) and cancer, respectively
(Table 6). STEP is a brain specific tyrosine phosphatase that is
elevated in AD patients. Recent work suggests that decreasing
STEP levels in the prefrontal cortex can mitigate the cognitive
deficits from AD. Furthermore, FAS is overexpressed in many
cancers and is believed to be essential for the growth of solid
tumors. It has been demonstrated that inhibition of FAS can
induce apoptosis in cancer cells. Accordingly, compounds that
exhibit selective inhibition of these targets could lead to ad-
vances in the development of drugs relevant to these diseases.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM 86192 and
GM 24539) and the Robert A. Welch Foundation (F-0652) for
their generous support of this work. We are also grateful to Dr.
Richard Pederson (Materia, Inc.) for catalyst support.
REFERENCES
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SUMMARY
■
We have prepared a 124-member library of novel norbenzo-
morphans by employing a sequential MCAP/RCM/Heck reac-
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ionic conditions. Utilizing a series of palladium catalyzed cross-
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ASSOCIATED CONTENT
■
S
* Supporting Information
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Experimental procedures, full characterization data, and
tabulated Lipinski parameters for representative compounds.
This material is available free of charge via the Internet at
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conformationally-constrained benzoxazocines and benzazocines via
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AUTHOR INFORMATION
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Corresponding Author
(9) (a) Donald, J. R.; Martin, S. F. Synthesis and diversification of
1,2,3-triazole-fused 1,4-benzodiazepine scaffolds. Org. Lett. 2011, 13,
852−855. (b) Donald, J. R.; Wood, R. R.; Martin, S. F. Application of a
sequential multicomponent assembly process/Huisgen cycloaddition
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/co300068a | ACS Comb. Sci. XXXX, XXX, XXX−XXX