Table 1.

Hypoxia Activated Prodrugs With Potential Anti-TB Applications

Compound	Mechanism of Action and Clinical Evaluation	Reference
TH-302 (Evofosfamide)	TH-302 is a 2-nitroimidazole HAP of bromo-isophosphoramide that is reduced via one-electron oxidoreductases to release a potent DNA alkylating agent bromo-isophosphoramide. This HAP showed clear evidence of selective eradication of hypoxic cells and good safety profiles in animals. TH-302 is undergoing several Phase III studies (MAESTRO; NCT01746979 and TH-CR-406/SARC021; NCT01440088).	[18]
EO9 (Apaziquone)	EO9 is an indolequinone of mitomycin C and its mechanism of action involves reduction by 1 and/or 2 electron oxidoreductases releasing DNA damaging species under aerobic and hypoxic conditions (Phillips). Although results of Phase II studies were disappointing, an explanation for the poor results was that the presence of hypoxia in the patient’s tumors were not included into the trial design. Two new Phase III trials used a new administration schedule (NCT00598806 and NCT00461591), and further Phase III study has been planned (NCT01410565).	[20]
AQ4N (Banoxantrone)	AQ4N is metabolized by cytochrome P450 and inducible nitric oxide synthase (iNOS) to an inhibitor of topoisomerase II. Its mode of action involves an initial 2 electron reduction step followed by further 2 electron reduction steps to generate AQ4. The compound is active in tumor cells, and hypoxic tumor-associated macrophages were induction of iNOS under hypoxic conditions reduces AQ4N, which kill tumor cells via a bystander effect. AQ4N has been evaluated in 3 Phase I studies.	[48]
PR-104	PR-104 undergoes rapid hydrolysis by phosphatases to generate PR-104A, which is metabolized by 1 and/or 2 electron oxidoreductases to facilitate interstrand DNA cross-linking. The compound penetrates severely hypoxic regions of tumors were this metabolized to cytotoxic metabolites. Based on preclinical data, a Phase I/II study has demonstrated good clinical activity.	[49]
Tirapazamine (TPZ)	TPZ is reduced by 1 electron oxidoreductases to generate a radical that, in the absence of oxygen, leads to the formation of DNA-damaging radicals. Whereas Phase I and II studies generated positive results, several Phase III clinical trials failed to demonstrate any survival benefit by adding TPZ to chemotherapy in non-small cell lung cancer, head and neck cancer, and cervical cancer. One reason for the failure of TPZ is lack of stratification of patients based on tumor hypoxia levels.	[21]
TH-4000 (tarloxotinib bromide)	In contrast to other HAPs that generate metabolites that damage DNA either directly or indirectly, TH-4000 is a hypoxia-activated EGFR tyrosine kinase inhibitor and is currently undergoing Phase II clinical evaluation (NCT02454842 and NCT02449681).	[18]
Myo-inositol trispyrophosphate (ITPP)	ITPP is a synthetic derivative of myoinositol hexakisphosphate, which is an allosteric effect of hemoglobin (Hb). By reducing the binding affinity of Hb to oxygen, oxygen is released, enhancing oxygen levels in the hypoxic environment, which inhibit hypoxia-induced angiogenesis. Notably, since ITPP accumulates in erythrocytes, increase oxygen release also occurs in vivo. ITPP display little in vivo toxicity, neither in animals nor humans. Currently, clinical trials are ongoing (NCT02528526). ITPP is exploited as a performance-enhancing doping agent, largely due to its capacity to increase oxygen availability during exercising.	[50]

Abbreviations: DNA, deoxyribonucleic acid; EGFR, estimated glomerular filtration rate; HAP, hypoxia-activated prodrug.