Tirapazamine

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Tirapazamine
Skeletal formula
Space-filling model
Clinical data
ATC code
  • none
Identifiers
  • 4-hydroxy-1-oxido-1,2,4-benzotriazin-1-ium-3-imine
JSmol)
  • C1=CC=C2C(=C1)N(C(=N)N=[N+]2[O-])O
  • InChI=1S/C7H6N4O2/c8-7-9-11(13)6-4-2-1-3-5(6)10(7)12/h1-4H,(H2,8,9) ☒N
  • Key:ORYDPOVDJJZGHQ-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Tirapazamine (SR-[[4233]]) is an experimental anticancer drug that is activated to a toxic radical only at very low levels of

radiotherapy and most anticancer drugs. Thus the combination of tirapazamine with conventional anticancer treatments is particularly effective. As of 2006, tirapazamine is undergoing phase III testing in patients with head and neck cancer and gynecological cancer, and similar trials are being undertaken for other solid tumor types.[1][2]

Chemically it is an aromatic heterocycle di-N-oxide. Its full chemical name is 3-amino-1,2,4-benzotriazine-1,4 dioxide. Originally it was prepared in a program screening for new herbicides in 1972. Its clinical use was first described by Zeman et al. in 1986.[3] While tirapazamine has had only limited effectiveness in clinical trials,[4] it has been used as a lead compound to develop a number of newer compounds with improved anti-cancer properties.[5]

An update of a Phase III trial (Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group) found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improved overall survival.[6]

Two possible molecular mechanisms of TPZ, for generating reactive oxygen species which causes DNA strand break, have been considered widely. In hypoxia, under bioreductive condition, it has been observed that TPZ primarily produces hydroxyl or and benzotriazinyl radicals as the DNA damaging reactive species.[7][8]

A new clinical phase I trial of Tirapazamine combined with embolization in liver cancer has been received in June, 2014. This study will help to optimize the safe tolerable dose of TPZ, when it is administered with embolization in liver cancer.[9] Treatment of solid tumors is complicated by the fact that these are often poorly provided with blood vessels, thus limiting their exposure to

nitroxide radicals on reduction.[citation needed
]

Synthesis

Tirapazamine synthesis:[10][11][12]

The first step in the synthesis, condensation of

2-nitroaniline (1) with cyanamide, probably involves initial formation of a guanidine such as 2. This then cyclizes to the heterocycle 3. Oxidation with hydrogen peroxide
then completes the preparation of tirapazamine (4).

References

  1. PMID 15379691
    .
  2. PMID 11894020
    .
  3. PMID 3744945
    .
  4. S2CID 71928597
    .
  5. PMID 18847185
    .
  6. PMID 20479425
    .
  7. PMID 19117394
    ..
  8. S2CID 3105010
    .
  9. ^ Clinical trial number NCT02174549 for "Dose-defining Study of Tirapazamine Combined With Embolization in Liver Cancer" at ClinicalTrials.gov
  10. doi:10.1039/J29700000911
    .
  11. doi:10.1039/JR9570003186
    .
  12. ^ K. Ley et al., DE 2204574 ; eidem, U.S. patent 3,868,371 (1973, 1975 both to Bayer).

External links

  • Clinical trial number NCT00033410 for "Chemotherapy, Tirapazamine, and Radiation Therapy in Treating Patients With Non-Small Cell Lung Cancer" at ClinicalTrials.gov
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