TY - DATA T1 - Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia-Selective DNA-Oxidizing Agent 3‑Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine) PY - 2015/12/17 AU - Kevin M. Johnson AU - Zachary D. Parsons AU - Charles L. Barnes AU - Kent S. Gates UR - https://acs.figshare.com/articles/dataset/Toward_Hypoxia_Selective_DNA_Alkylating_Agents_Built_by_Grafting_Nitrogen_Mustards_onto_the_Bioreductively_Activated_Hypoxia_Selective_DNA_Oxidizing_Agent_3_Amino_1_2_4_benzotriazine_1_4_Dioxide_Tirapazamine_/2037927 DO - 10.1021/jo501252p.s002 L4 - https://ndownloader.figshare.com/files/3609231 KW - Agent KW - tirapazamine analogues KW - hypoxic KW - Grafting Nitrogen Mustards KW - dioxide KW - tirapazamine analogue 18 KW - nitrogen mustard units KW - deoxygenation KW - nitrogen mustard unit KW - Hammett sigma values N2 - Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells. ER -