Abstract
We presented here design, syntheses and inhibitory activities of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-Trp as an IDO affinity moiety without inhibitor 1MT, such as L-Trp-TPZ hybrids 1 (TX-2274), 2 (UTX-3), 3 (UTX-4), and 4 (UTX-2). TPZ-monoxide hybrids 1 and 3 were good competitive IDO inhibitors, while TPZ hybrids 2 and 4 were uncompetitive IDO inhibitors. Among them TPZ-monoxide hybrid 1 have the strongest IDO inhibitory activity. It suggests that TPZ-monoxide hybrids 1 and 3 are able to bind the active site of IDO, TPZ hybrids 2 and 4 are able to bind the enzyme-substrate complex. We proposed the possible mechanism of action of TPZ hybrid 2 that may first affect as a hypoxic cytotoxin, and then metabolized to TPZ-monoxide hybrid 1, which may do as an IDO inhibitor more effectively than its parent TPZ hybrid 2.
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Acknowledgments
The authors thank Ms. M. Nakamura, Ms. K. Yamashita, Ms. E. Okayama and the staff of our Faculty for measurement of NMR, MS and elemental analyses.
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Nakashima, H. et al. (2010). Design of Novel Hypoxia-Targeting IDO Hybrid Inhibitors Conjugated with an Unsubstituted L-TRP as an IDO Affinity Moiety. In: Takahashi, E., Bruley, D. (eds) Oxygen Transport to Tissue XXXI. Advances in Experimental Medicine and Biology, vol 662. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-1241-1_60
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DOI: https://doi.org/10.1007/978-1-4419-1241-1_60
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