Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity

Abstract

Tirapazamine (TPZ) and related 1,2,4-benzotriazine 1,4 dioxides (BTOs) are selectively toxic under hypoxia, but their ability to kill hypoxic cells in tumors is generally limited by their poor extravascular transport. Here we show that removing hydrogen bond donors by replacing the 3-NH2 group of TPZ with simple alkyl groups increased their tissue diffusion coefficients as measured in multicellular layer cultures. This advantage was largely retained using solubilizing 3-alkylaminoalkyl substituents provided these were sufficiently lipophilic at pH 7.4. The high reduction potentials of such compounds resulted in rates of metabolism too high for optimal penetration into hypoxic tissue, but electron-donating 6- and 7-substituents moderated metabolism. Pharmacokinetic/pharmacodynamic model-guided screening was used to select BTOs with optimal extravascular transport and hypoxic cytotoxicity properties for evaluation against HT29 human tumor xenografts in combination with radiation. This identified four novel 3-alkyl BTOs providing greater clonogenic killing of hypoxic cells than TPZ at equivalent host toxicity, with the 6-morpholinopropyloxy-BTO 22 being 3-fold more active.

Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

“…In an attempt to overcome pharmacokinetic limitations associated with first generation hypoxia-selective redox chemotherapeutics, recent drug discovery has focused on the identification of novel agents with optimized extravascular transport and antitumor activity including 6-morpholinopropyloxy-1,2,4-benzotriazine 1,4-dioxide ( Fig. 16-82) that display enhanced HCRs as determined in specialized three-dimensional cell culture models and tumor xenografts (145,146,148).…”

Hypoxia-Activated Prodrugs in Cancer Therapy: Progress to the Clinic

“…The hypoxic cell kill of TPZ analogs was shown to be very sensitive to changes in D MCL , making optimization of this parameter also of impor� tance [38]. Thus, replacing the 3�amino group of TPZ with lipophilic 3�alkylaminoalkyl sub� stituents provided compounds with improved solubility and D MCL values [40]. Addition of electron�donating groups at the 6� or 7�posi� tions, to compensate for the resulting higher reduction potential, gave compounds such as the 6�morpholinopropyloxy analog ( Figure 1C), which showed greater killing of hypoxic cells in HT29 human tumor xenografts than TPZ did (1.66 vs 0.59 logs of hypoxic cell kill) at equivalent host toxicity levels [40].…”

Role of PhaseIMetabolism in Drug Activation and Clinical Treatment Outcomes

“…Such prodrugs include nitroarenes, quinones, amidoximes, platinum(IV) complexes, and N-oxides exemplified here with tirapazamine (36 in Fig. 10.12) [124][125][126][127][128].…”