Synthesis and biological activity of 1-methyl-tryptophan-tirapazamine hybrids as hypoxia-targeting indoleamine 2,3-dioxygenase inhibitors

Bioorganic & Medicinal Chemistry
Hitomi NakashimaHitoshi Hori

Abstract

We have designed and synthesized new hypoxic-neoplastic cells-targeted indoleamine 2,3-dioxygenase (IDO) inhibitors. 1-Methyl-tryptophan (1MT)-tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-dioxide) hybrid inhibitors including 1 (TX-2236), 2 (TX-2235), 3 (TX-2228), and 4 (TX-2234) were prepared. All of these compounds were uncompetitive IDO inhibitors. TPZ-monoxide hybrids 1 and 3 showed higher IDO inhibitory activities than TPZ hybrids 2 and 4. Among these hybrids, hybrid 1 was the most potent IDO inhibitor. TPZ hybrids 2 and 4 showed stronger hypoxia-selective cytotoxicity than TPZ to EMT6/KU cells. These data suggest that TPZ hybrids 2 and 4 may act through their dual biological functions: first, they function as hypoxic cytotoxins in hypoxic cells, and then are metabolized to their TPZ-monoxide (3-amino-1,2,4-benzotriazine 1-oxide) hybrids, which function as IDO inhibitors.

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Citations

Aug 10, 2010·The Cancer Journal·Hatem SolimanScott Antonia
Feb 17, 2015·Future Medicinal Chemistry·Tianze JiangZhiyu Li
May 16, 2017·MedChemComm·Alice ColettiAntonio Macchiarulo
Dec 24, 2018·Chemical Society Reviews·Amit SharmaJong Seung Kim
Mar 21, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hongchuan ZhaoChunyong Ding
Dec 21, 2020·European Journal of Medicinal Chemistry·Rahul Singh, Deepak B Salunke
Jan 9, 2010·Journal of Medicinal Chemistry·Ute F RöhrigOlivier Michielin
May 15, 2015·Journal of Medicinal Chemistry·Ute F RöhrigOlivier Michielin
Jan 29, 2011·Bioorganic & Medicinal Chemistry·Eduard DolušićRaphaël Frédérick

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