Hypoxia-activated prodrugs

A series of achiral hypoxia-activated prodrugs were synthesized on the basis of ifosfamide. Prodrugs, activated by 2-nitroimidazole reduction, demonstrated up to 400-fold enhanced cytotoxicity toward H-460 cells in culture under hypoxia versus their potency under aerobic conditions. The lead compound (75) has also been stable to liver microsomes and is currently being evaluated in the clinic as a promising antitumor agent. 

W.R. Wilson, M. Tercel, R.F. Anderson and W.A. Denny, Radiation-activated prodrugs as hypoxia-selective cytotoxins model studies with nitroarylmethyl quaternary salts, Anti-Cancer Drug Des., 13 (1998)663. 

Tumor hypoxia and bioreductive activation of anticancer prodrugs... 

Tumor Hypoxia and Bioreductive Activation of Anticancer Prodrugs... 

Tumor-activated anticancer prodrugs based on hypoxia... 

Tumor-Activated Anticancer Prodrugs Based on Hypoxia... 

Hypoxia appears to be a common and unique property of cells in solid tumors and is a target for tumor-specific activation of anticancer prodrugs.4 It is now well known that solid tumors often contain an inefficient microvascular system, and part of solid tumors exists under a hypoxic condition.12 Hypoxia can be classified into two broad types chronic and acute. Chronic hypoxia occurs in cells that are distant from their blood supply and suffer low oxygen tension permanently. Acute hypoxia results in cells experiencing temporary cessation of blood flow. 

Hypoxia of solid tumors has been exploited in designing hypoxia-selective anticancer dmgs or prodrugs. In particular, the elevated activities of various reductive enzymes under a hypoxic condition have been extensively targeted for tumor-selective prodrugs. Another feature associated with hypoxia is low extracellular pH.15 This is likely to be a result of an insufficient blood supply that leads to the accumulation of acidic metabolites. Anticancer prodrugs activated in a low-pH environment have also been reported.16... 

Activation of prodrugs in hypoxia or anoxia by chemical reduction without fragmentation... 

Harada H, Kizaka-Kondoh S, Itasaka S, et al. The combination of hypoxia-response enhancers and an oxygen-dependent proteolytic motif enables real-time imaging of absolute HIE-1 activity in tumor xenografts. Biochem Biophys Res Commun 2007 360 791-7%. Inoue M, Mukai M, Hamanaka Y, Tatsuta M, Hiraoka M, Kizaka-Kondoh S. Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites. Int J Oncol 2004 25 713-720. 

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