Design of Novel Hypoxia-Targeting IDO Hybrid Inhibitors Conjugated with an Unsubstituted L-TRP as an IDO Affinity Moiety
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.
KeywordsCDCl3 CH2Cl2 Indole Kynurenine Indoleamine
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.
- 3.D. Y. Hou, A. J. Muller, M. D. Sharma, J. DuHadaway, T. Banerjee, M. Johnson, A. L. Mellor, G. C. Prendergast, D, H. Munn, Inhibition of Indoleamine 2,3-Dioxygenase in Dendritic cells by Stereoisomers of 1-Methyl-Tryptophan Correlates with Antitumor Responses, Cancer Res. 67, 792–801 (2007).PubMedCrossRefGoogle Scholar
- 5.M. P. Hay, K. O. Hicks, F. B. Pruijn, K. Pchalek, B. G. Siim, W. R. Willson, W. A. Denny, Pharmacokinetic/Pharmacodynamic Model-Guided Identification of Hypoxia-Selective 1,2,4-Benzotriazine 1,4-Dioxides with Antitumor Activity: The Role of Extravascular Transport, J. Med. Chem. 50, 6392–6404 (2007).PubMedCrossRefGoogle Scholar
- 7.H. Nakashima, Y. Uto, E. Nakata, H. Nagasawa, K. Ikkyu, N. Hiraoka, K. Nakashima, Y. Sakaki, H. Sugimoto, Y. Shiro, T. Hashimoto, Y. Okamoto, Y. Asakawa, H. Hori, Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors, Bioorg. Med. Chem. 16, 8661–8669 (2008).PubMedCrossRefGoogle Scholar