Simple Synthesis of 3‐Amino‐1,2,4‐benzotriazine 1,4‐Dioxide

Seng, Florin; Ley, Kurt

doi:10.1002/anie.197210092

Cited by 18 publications

(10 citation statements)

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“…Tirapazamine, SR 4317, SR 4330 and RSU 1069 were synthesized in house using previously described methods (Seng and Ley, 1972;Adams et al, 1984). NADPH was purchased from Boehringer Mannheim (Lewes, UK), HPLC grade methanol was purchased from Merck (Lutterworth, UK).…”

Section: Materials and Methods Chemicalsmentioning

confidence: 99%

Overexpression of human NADPH:cytochrome c (P450) reductase confers enhanced sensitivity to both tirapazamine (SR 4233) and RSU 1069

Patterson

Saunders²,

Chinje³

et al. 1997

Br J Cancer

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Summary P450 reductase (NADPH: cytochrome c (P450) reductase, EC 1.6.2.4) plays an important role in the reductive activation of the bioreductive drug tirapazamine (SR4233). Thus, in a panel of human breast cancer cell lines, expression of P450 reductase correlated with both the hypoxic toxicity and the metabolism of tirapazamine Br J Cancer 72: 1144-1150. To examine this dependence in more detail, the MDA231 cell line, which has the lowest activity of P450 reductase in our breast cell line panel, was transfected with the human P450 reductase cDNA. Isolated clones expressed a 78-kDa protein, which was detected with anti-P450 reductase antibody, and were shown to have up to a 53-fold increase in activity of the enzyme. Using six stable transfected clones covering the 53-fold range of activity of P450 reductase, it was shown that the enzyme activity correlated directly with both hypoxic and aerobic toxicity of tirapazamine, and metabolism of the drug under hypoxic conditions. No metabolism was detected under aerobic conditions. For RSU1069, toxicity was also correlated with P450 reductase activity, but only under hypoxic conditions. Measurable activity of P450 reductase was found in a selection of 14 primary human breast tumours. Activity covered an 18-fold range, which was generally higher than that seen in cell lines but within the range of activity measured in the transfected clones. These results suggest that if breast tumours have significant areas of low oxygen tension, then they are likely to be highly sensitive to the cytotoxic action of tirapazamine and RSU 1069.Keywords: P450 reductase; hypoxia, bioreductive drugs; tirapazamine; RSU 1069; breast cancer It is now well established that regions of low oxygen tension (hypoxia) can exist in many human solid tumours and that this hypoxia can sometimes predispose to failure of some treatments with radiotherapy (Hoeckel et al, 1996). One of the reasons for this failure is likely to be the inherent radiation resistance of hypoxic cells. One strategy being developed to overcome this problem is via the use of drugs that will selectively kill hypoxic cells Stratford, 1986, 1994;Zeman et al, 1986;Kennedy, 1987;Brown and Siim, 1996;Denny et al, 1996). This approach involves the exploitation of various biochemicla processes that, at low oxygen tensions, can result in selective reductive activation of a prodrug to give cytotoxic species (Workman and Stratford, 1993 enzymes. Thus, it has been proposed that hypoxic cells could be more effectively targeted if differences in the levels of the reductases in various cell types were taken into account to direct appropriate agents to particular human tumours based on their enzymology Workman and Stratford, 1993). Patterson et al (1995) examined the possible application of the enzyme-directed approach to the development of tirapazamine. The metabolism of this agent was suggested to be dependent on the presence of P450 reductase (Walton et al, , 1992. In a panel of six breast cancer cell lines with a sixfold range in P450 red...

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Section: Materials and Methods Chemicalsmentioning

confidence: 99%

Overexpression of human NADPH:cytochrome c (P450) reductase confers enhanced sensitivity to both tirapazamine (SR 4233) and RSU 1069

Patterson

Saunders²,

Chinje³

et al. 1997

Br J Cancer

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“…Drug Kirihata and his colleagues synthesized BPA-ol from N-formyl-BPA ethyl ester or BPA as a starting compound through alcohol or BPA ester formation, respectively, to develop a new BPA analogue with high water solubility. 2,3) Hori, Nagasawa and Uto synthesized TPZ according to the established method, 12) which Brown and colleagues also employed, 13) and analyzed it by chemical ionization mass spectrometry [m/z, 179(MH+)], electron ionization mass spectrometry [m/z, 178(M+)] and infrared spectrometry [KBr]. This synthesized TPZ was regarded as identical to commonly used TPZ.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the Potential of p‐Boronophenylalaninol as a Boron Carrier in Boron Neutron Capture Therapy, Referring to the Effect on Intratumor Quiescent Cells

Masunaga

Ono

Kirihata

et al. 2001

Japanese Journal of Cancer Research

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were determined from tumors that were not pretreated with BrdU. Without TPZ or MTH, BPA-ol increased both frequencies most markedly, especially for total cells. However, as with BPA, the sensitivity difference between total and Q cells was much larger than with BSH. On combined treatment with both MTH and TPZ, this sensitivity difference was markedly reduced, similarly to when BPA was used. MTH increased the 10 B uptake of all 10 B-compounds into both tumor cells. BPA-ol has good potential as a 10 B-carrier in neutron capture therapy, especially when combined with both MTH and TPZ.

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“…The 10 B concentration in the tumors was measured by prompt γ-ray spectrometry using a thermal neutron guide tube at KUR. 12) Hori synthesized TPZ according to the established method, 13) which Brown and colleagues also employed, 5) and analyzed it by using chemical ionization mass spectrometry [m/z, 179(MH+)], electron ionization mass spectrometry [m/z, 178(M+)] and infrared spectrometry [KBr]. This synthesized TPZ was concluded to be identical with commercial TPZ.…”

Section: Methodsmentioning

confidence: 99%