Electron Transfer and Oxidative Stress as Key Factors in the Design of Drugs Selectively Active in Hypoxia.

Abstract

Hypoxia is a feature of some regions of many tumours, ischaemic events, and arthritis. Drugs activated in hypoxia have wide potential application, particularly in overcoming the resistance of hypoxic tumour cells to radiotherapy. Key features of such drugs include redox properties appropriate for activation by reductase enzymes (typically flavoproteins), and oxygen-sensitive reduction chemistry such that normal levels of oxygen inhibit or reverse reduction. In many cases this selectivity is achieved by a fast, free-radical reaction in which the drug radical (often an obligate intermediate in drug reduction) reduces oxygen to form superoxide radicals and thus 'futile cycles' the drug in normoxic tissues. However, this enhances cellular oxidative stress, which may be linked to normal tissue toxicity. Appropriate redox properties are found with nitroarene, quinone, or aromatic N-oxide moieties. A particularly promising and versatile exploitation of bioreductive activation is for reduction of such 'triggers' to activate release of an 'effector', an agent that can obviously be active against diverse conditions associated with hypoxia. The same approach can also be used in diagnosis of hypoxia. Much information concerning the reactions of intermediates in drug action and the quantitative prediction of redox properties of analogues has been accrued. Drug design can be mechanism-led, with the wealth of literature quantifying redox properties of drug candidates a rich source of potential new leads. There is a clear appreciation of the kinetic factors that limit drug efficacy or selectivity. Thus the potential for rapid expansion of these concepts to diverse diseases is considerable.

1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine: An anticancer agent targeting hypoxic cells

“…The conversion of the nitro substituent of KS119 to a hydroxylamino group probably begins with the input of a single electron, followed by protonation and disproportionation and further reduction as described by Knox et al (16); thus, the initiating enyzmes are one-electron-reducing systems. Under aerobic conditions the input of the initial electron produces the nitro radical anion, which is rapidly scavenged by oxygen (15). This phenomenon results in redox cycling that regenerates the parental prodrug and forms superoxide.…”

“…Under aerobic conditions, the nitro radical anion is rapidly back-oxidized by O 2 to regenerate the inactive prodrug form and O 2 ⅐Ϫ , resulting in an undetectably low steadystate concentration of nitro radical anions (15). However, under hypoxic conditions, the nitro radical anion probably undergoes disproportionation and further reduction through the addition of successive electrons to produce nitroso, hydroxylamino, and amino species, as demonstrated by p-substituted nitrobenzenoids (16).…”

Prediction of Tumour Tissue Diffusion Coefficients of Hypoxia-Activated Prodrugs from Physicochemical Parameters

“…The D mcl values for urea were determined by fitting the flux data to MCLs for which thicknesses were subsequently determined by microscopy, expanding on previous determinations. [38] The urea D mcl values (mean ± s.e.m., [n], cm 2 s −1 × 10 7 ) were 4.50 ± 0.23 [6] for HT29, 9.62 ± 0.85 [9] for SiHa, 1.31 ± 0.37 [15] for HCT8-Ea, and 26.8 ± 0.72 [13] for HCT8-Ra. Flux through bare support membranes was also evaluated for each compound to confirm stability and to check that diffusion coefficients through the support membrane (porosity 11%) were consistent with MW.…”

“…[10] At the same time the presence of more severe and extensive hypoxia in tumours than in normal tissues provides a physiological target that can potentially be exploited as a basis for tumour selectivity. [3,[11][12][13][14][15][16] Several prodrugs that are selectively activated under hypoxia are currently in clinical or preclinical development, [17][18][19][20] including the benzotriazine-di-N-oxide tirapazamine (TPZ; Fig. 1).…”

Potent antileukemic action of naphthoquinoidal compounds: evidence for an intrinsic death mechanism based on oxidative stress and inhibition of DNA repair

“…1,2 Studies of the antitumor properties and mechanisms of action of quinone derivatives have shown that they can act as topoisomerase inhibitors via DNA intercalation, and their toxicity can also be explained by oxidative stress with reactive oxygen species (ROS) generation, which are usually toxic to normal tissues, thus reducing the therapeutic utility of quinones. [3][4][5] Despite recent technological advances, cancer treatment remains a challenge, and, in some circumstances, a complete remission is difficult to achieve. Currently, the investigation of natural products and chemical modifications to antitumor substances are among the most important strategies used in the search for new antineoplastic drugs.…”