Home / papers / Redox Potentials of ProDrugs Based On Density Function Theory Research Paper

Redox Potentials of ProDrugs Based On Density Function Theory Research Paper


The bioreversible derivatives of drug that alters the enzymatic and chemical component of medicines and yield active products regarded as prodrugs involve either oxidation or reduction processes.  Such processes generate intended pharmacological effect of the drug component’s methods for clinical purposes.  The adoption of the prodrug in the analysis of redox potential with the DFT has facilitated the advancement inaccurate examination and manufacture of physiochemical products at the same time improved both biopharmaceutical and pharmacokinetic characteristics of relevant pharmacologically active agents. The research paper focuses on the integration of prodrug concept in the design and production of drugs under the influence of modern technological advancement in the field of medicine. The process of prodrug design involves a chemical transformation that is slowly gaining entry in the drugs that are undergoing human trials. The process takes into consideration the increased potency of the pharmaceutical aspect of narcotics that would otherwise fade off under standard combinational chemical processes of a drug formulation. The adoption of prodrug process eliminates potential deterrence in the formulation and delivery attributed to inadequate aqueous solubility, instability of chemical components, poor oral absorption, faster pre-systemic metabolism, higher rates of toxicity and insufficient penetration in other body tissues. The prodrug designs utilize a simple combination of a limited number of chemicals or enzyme alterations of the principle active component to generate active drugs where individual molecule operates as a promoietry on the other through derivatives regarded as co-drugs. The paper unearths the principles adopted in the new design of oxidation or reduction processes utilized in the modification of compounds metabolically or chemically to produce desired drugs targeting specific tissues. Prodrugs differ from soft drugs in that they never undergo predictable and controllable metabolism after attaining therapeutic status.

Speech about the Research

The current progress in clinical medicine based on the improved technology and Nanomedicine influenced the research on the calculation of bio-oxidation or reduction activities in prodrug examinations within the pharmaceutical field. Top medical research institutions collectively initiated the research on the prodrug performance intended to minimize the development of drug resistance by some disease causing pathogens. The performance of biological nanomachines introduced in medicine improves the data, and patient analysis thus extends both the quality and length of life. On the same way, the presence of nanotechnology provides relevantly engineered drugs with minimal traces of cancer seeking missiles. The molecular improvement of prodrug analysis provides relevant and improved medications that help in reducing the effect of drug resistance. [2] Superior nations often considered the improved technology as a technology geared to the innovation of molecular computers. In the present and subsequent years, the research funding about the prodrug development steadily increased.

The funding of the investigation on molecular modeling has grown by 28% every year. Increased interest in the application of technological findings led to the creation of Nanomedicine a branch of medicine that analyses the progress of technology in drug development. The prodrug concept adopts overlapping advancements by tackling medical problems through the adoption of nanoscale structured materials and existing simple nanodevices. The research reveals the intended impact of biotechnology that will advance molecular medicine through improved prodrug developments as well as biobotic. The projection of involvement of nanorobots in the field of medicine will offer an optimal tool to physicians intended to conquer human disease. Analysis of the preceding three fundamental ideologies acts as indicators of the improved technology that influences the DFT calculations of prodrugs performance designed to minimize the chances of disease resistance as observed in the clinical administration of drugs. [6] The concept accelerated the development of microcapsules with replaceable islets used in the treatment of diabetes patients’ and temporarily restore delicate glucose control feedback loop without immunosuppressant that leaves the victim in serious risks of infection.

The process may treat other cases of enzyme or hormone deficiency. The presence of active biological noncensors within the DNA accelerates drug separation and oxidation processes done under the prodrug calculations. The adoption of Ambri biosensors detects slightest changes in the chemical concentration of drug components. The research further considered the impact of electrical fields in accelerating the RNA and DNA polymers to the centralized nanopores protein component attached to the lipid bilayer of the outer membranes of the living cells. The existence of binding sites attributed to the ionization concepts of either cation or anion increases the electron transfer from one component to the next thus shifts the resultant chemical characteristic of the product. Most of the research conducted by the medical scientists unearths the probable and optimal possible application of the molecularly imprinted polymer in clinical fields like the ability to regulate drug emission, receptor and enzyme mimics.

Prodrug applications eliminate the probable inaccuracies attributed to disease resistance witnessed during drug administration. Resultant prodrugs have reduced active time compared to the conventional drugs, for instance, the use of microbivores accomplishes treatment of septicemic infection in minutes or hours compared to the use of antibiotics that require weeks or months in achieving total clearance of targeted bacteria from the blood system of patients. In every cycle of operation, the bacterium bonds to the surface of the microbivore through specific binding sites thus deliver the pathogen to the ingestion port in front of the device. [3] The increased trends in the cost of drugs compelled the medical practitioners and research team to act on the most efficient prodrugs that provide precise and optimal feedbacks during clinical trials of the products. The inclusion of computer aided structural design of prodrugs increases the ease of generation of drugs with complex structures like those of the lipophilic aryl rings. During prodrug formation, all algorithms in question must undergo rigorous tests to eliminate the possibility of a product failure during the trial case stage. Some of the critical tests of algorithm take into account the summation of the biological effect of used clinical drugs.

Cases of poorly formulated prodrugs result in more deaths among the patients. Therefore the drug discovery either through oxidation of reduction processes requires utmost care in the development of a workable algorithm to generate safe and suitable products for use in the clinical setups. Qualitative testing of the prodrug is critical in running drug tests without sidelining the challenge of accurate data collection process. Application of known prodrugs reflects on the accuracy with which global advancement in clinical medicine development occurs through the adoption of robust algorithms and the adopted methodology in the research yields vital tools for bio-oxidation of known drug samples. The selected drug bank provided necessary volumes of data desirable for the entire study session of the prodrug calculations based on the DFT procedures. Gaussian software adopted sustained robust analysis and integration of findings for amicable solution generation desired in the medical field. [1]



The adoption of ring cleavage of benzene, toluene under DOAS (differential absorption spectroscopy) facilitated the use of simulation, measurement of prodrug redox potential within the retention rings of the product observed in a series of simulation chambers. The time resolution of the product facilitated principle formation of ring cleavage around the products that disintegrate from other pathways through the reaction of stable intermediate components under secondary glyoxal formation. The principle prodrug products emanating from the oxidation and radiation process are the ring retaining and glyoxal. The two products are formed over the experimental time scale with minimal influence as opposed by the secondary glyoxal pathway. The preliminary investigations revealed that the oxidation and radiation of branching aromatic OH in the atmospheric oxygen produce benzene systems called hydroxy-cyclohexadienyl radical. The branching ratio of compounds has little influence on the byproduct due to the attributed difficulty hindering direct observation of their impact on the system.  The unpredictability of particular prodrug formation pathways deters precise determination of mechanistic product of stable intermediate compounds reflected by the DOAS. The concept of prodrug utilizes the existing drugs to improve their quality and active parts through oxidation or reduction process. [8]

One- Electron Bio-Oxidation

The process of drug formulation through prodrug principles involve electron reduction under the process of pulse radiolysis thus produces radical anions with absorption bands within visible spectrums. The anions attain kinetic transformation of the first redox with weaker absorption transient that dies off after a lengthy timescale elapse. The use of benzyl viologen scale revealed the equilibrium point of electron transition in the drug compounds. The adoption of cloned and purified drug components influences the anaerobic status of the redox active species. Reduction of an electron from the ring and rearranging the alkylation reflect a tautomerized characteristic of resultant drugs as all structures possess equal energy levels. The resulting semiquinone may yield quinine-methide species in an endothermic process. The energy changes that occur in the process are equal to the quantities absorbed in the process of nucleophilic attack that favors carbon chain depletion. Subsequent oxidation results in distinct hydroquinone. [17; 8]  The occurrence of oxidation by molecular oxygen replaces the DNA due to inadequate enzyme accessibility, hence terminated the entire process of prodrug activity.

Considering an initial hyperfine spectrum in the analysis of redox potential through accumulating spectrum generates an overlapping range of higher carbon chain concentration for the phenyl species. The inclusion of oxides in the system reflects increased radical reaction of the compounds to produce the methyl component of the compounds thus raises the hydrogen atom from methanol. [12] High DMSO and methanol in the mixture scavenge hydroxyl radicals formed during the hemolytic fumigation of nitrogen-oxygen bonds to the retard addition of radicals to the unsaturated rings of carbon-centered atoms.

The fragmentation of N-O bonds involved the DFT (Density Function Theory) calculations facilitated the investigation of the observable disintegration of drug compounds to produces desired active parts of the chemicals. The presence of compounds with strong electron affinity facilitated the process of electron transfers within the drug components. For instance,  the trifluoromethyl moiety promotes radical anion transfer through the effective elimination of water elements from the BTZ radicals with a calculated energy value of 10.9kcal/mol depending on the spectra simulation of smaller quantities of aryl radicals. [2]



Time Scale for Product Formation

The presence of OH-radical abstraction reaction with an aromatic compound leads to the formation of aldehyde compounds. The reaction occurs under a minimal ppb forming an aldehyde-type of product closer to unity yield. The resulting aldehyde compounds are the primary products of the prodrug decay process. The presence of phenol-type constitutes the essential product of benzene as the formation of phenols directly inconsistency with an aromatic reaction of OH +O2 = phenol +OH2 in the case of toluene8 and p-xylene10.  The delayed response generated phenol as the primary product. [9] The process of redox reaction and oxidation influences the functions of intermediate species within the system. Faster rates of reaction depend on the available kinetic energy of the compounds. The upper limits of OH loss rates often remain constant in the experimental setups. Significantly delayed product formation affect the overall lifetime in the experimental measurement of the resulting prodrug compounds. Any excellent combination of carbon compounds releases a significant compound at the end of the oxidation process, and the stable intermediates produce a limited amount of secondary products, and the observation made following a linear increment while the explanation of entire process relied on the primary components.

Prodrug Design Concept

The design of prodrugs occurs at the initial stages of preclinical observations of the drug performance. The report considers the critical determinants that influence the structural design of prodrug structures. For instance, the parent drug selection needs to take into account the functional group of the chemical derivation intended for alteration with the aim of generating a new product. The concept of promoiety requires the product to grant user safety and ease of extraction from the body. Such choices rely on the nature of disease intended, dose and duration of drug administration. The characteristics of the parent and prodrug must be comprehensively analyzed to provide precise ADME (Absorption, distribution, metabolism and excretion) and pharmacokinetic features of drugs applicable in clinical setups. Degradation by-products are an essential prodrug design tool that is critical in understanding both chemical and physical stability that form degradable products. A larger percentage of prodrug components derived from organic compounds relied on activation facilitated by enzymatic hydrolysis through enhanced lipophilicity that produces water soluble drugs with straightforward synthesis processes. Some alkyls and aryl-based prodrugs have acquired a significant stake in the pharmaceutical industry.  The adoption of prodrug formulation improves water solubility through introduced ionizable parent drug thus facilitate parental administration. [15, 10]

Site-Selective Drug Delivery

Selectivity of the drug is the core characteristic of a prodrug that is necessary for reaching the targeted region. Site selection may occur passively as the drug reaches the intended organ. The transporter facilitated delivery through selective metabolism activated by antigen or enzymatic activities in the body. [14]

Density Function Theory

The theory explores four principle components of clinically acceptable drugs. That is the dipole moment (DM) Polaris-ability characteristic of drug (POL), Ionization potential (IP) and electron affinity (EA). The DM and POL have a direct relation to the cell membrane permeability of drugs whereas the IP and EA reflect the redox stability of medicines that influences the metabolism rates.  The use of a quantum chemical calculator in clinical chemistry facilitates precise investigation of and research on the prominent chemical compounds desired in the pharmaceutical industry. The study of drug-receptor and protein-ligand energies enables the students to understand the process of drug development and applications in clinical settings. [11]


Optimal investigation of redox potential from calculated DFT involves the collection of massive volumes of data regarding smaller molecular drugs generated from the reputable databank from the drug bank websites. The data structural composition comprises heavy metals, purely organic and inorganic salts, iodine and other mixtures of active compounds. Modification of some sampled drugs was through protonation and hydrolysis processes.  Due to the bulkiness of data designated for analysis application of the Gaussian analytical software proved to be quite relevant to the investigation of such nature. Both the adiabatic IP and EA resulted from convergence issues. [7] The paper explores the applicability of MS Office Excel alongside the QI Macros statistical software to facilitate data analysis and generate relevant and reliable predictions applicable in pharmaceutical industries during oxidation and reduction processes.

Experimental Selection

The analytical grade reagents adopted in the research were from the Riedel- de Haen and phosphate buffers from Merck. Most of the solutions used in the experiment originated from water solvent obtained from the Milli-Q purification system and the adjustment of the pH of the solution adjusted using phosphate salts. Adoption of linear accelerators delivered absorbed doses to sustain a spectral analysis for the kinetic energy investigation at room temperatures. [16]


Random sampling adopted in the study is likely to generate particular figures that once tested under the correlation tool eliminate probable discrepancies encountered during the experimental investigation as well as the theoretical analysis of the available data. [12] The presence of table and graphs facilitate data interpretation and deduction of intended findings.



The results reveal the DM values of correlation for experimental and calculated confirm the adoption of adequate theoretical assumptions in the paper throughout the investigation regarding the performance of prodrug analysis. The existence of the correlation value between the conceptual and experimental DM values depicts better correlation thus facilitate the understanding of POL correlations. [4]

Table: Correlation between experimental and theoretical data [5]

r2 n Slope (a) Intercept (b)
DM (D) 0.951 201 0.998 0.002
POL (A3) 0.935 120 0.784 -0.431
IP (eV) 0.964 215 0.962 -0.012
EA (eV) 0.782 90 0.976 -0.121

Comparative values explored through the adoption of different statistical models in a case where the IP value tends to be closer to a unity figure, then the correlation is good the EA values for organic based drugs are often positive and corresponds to the endothermic reduction process occurring in the oxidation process of prodrug development.  The presence of outliers in the data affects the correlation values. Adoption of corrected and compiled values provided a higher level of confidence with the approval of the DFT approach selected during the investigation of prodrug oxidation and reduction. [17]

The statistical distribution of the DM drug data reflects the abnormal distribution that shifts the distribution curve to the left resulting in a long-tailed graph with relative standard deviation of 3.0 that is closely related to the DM distribution curve based on the semi-empirical methods. Analysis of the existing data presented that that 95 percent of the drugs under investigation has DM of less than 10.0 and the finding offers a reflection of effective membrane permeability. [1] As the POL shift towards lower values, concentrating 95% of data to fall below 68.0A3

Table: Statistical variables [5]

mean SD 50% 95%
DM (D) 4.7 3.3 2.5 -5.9 10.0
POL (A3) 33.7 18.2 23.2 -40.2 66.0
IP (eV) 7.8 1.0 6.8 -7.8 6.1 -9.1
EA (eV) 0.3 1.2 -0.4 -1.1 -1.6 -2.1

Further examination of sampled data was from oral bioavailability. The available information from the drug bank proves relevant for the research into the prodrug performance. In both cases, the available evidence regarding oral absorption and bioavailability fell into the rating as either weak or low. While, the data for drugs used for respiratory or topical cases were not analyzed. Drugs with better oral absorption presented clear trends of DM and POL data values. [3]

Action on the Halogens

Approximately thirty percent of the sampled drugs data used in the study contain significant quantities of halogen moieties. Chlorine constituted a critical component of most tested drugs. The existence of heavier halogens in the system increases the lipophilicity of the drugs under investigation.  Current development limits the use of heavy halogens but considers alternatives of lower molecular weights. [9]

Therapeutic Application and Administration of Prodrug DFT

The understanding of administration correlation weights the existing drug compounds against the available drug components. The current trends subject the operators into daring conditions as 18 percent of antibiotic drugs contain sulfur compounds.  Other categories requiring therapeutic applications, utilized the existing components of available drugs. [14]


The adoption of quantum chemical analysis of initial concepts based on the experimental drug like dataset treats all compounds in a similar manner and adopts the DFT values as molecular descriptors. The theoretical approach involved the idea of simulation of the quantum chemical calculation involving the continuum salvation models that accounts for diverse interaction, unlike hydrogen bonding. The protonated part of drugs are the relevant components meant for water simulation that in turn needs a higher affinity for hydrogen thus shifts the calculated properties of drugs. The DM component exploits the molecular flexibility of medicines under experiment. Reduced DM values reflect increased lipid compatibility of the prodrug composition leading to improved permeability cases. The conventional drugs have an average of seven rotatable bonds. Some correlation techniques adopted in the semi-empirical processes help in the prediction of computational properties applicable to the determination of DFT. [11]

From the investigation, certain enzymatic activities like the cytochrome P450 facilitate up to the tune of 75% drug metabolism through a redox mechanism. Thus facilitating pertinent analysis of the effect of both IP and EA on drug compounds using wave functions that follow on semi-empirical methods to help in the justification and adoption of DFT.  The statistical data revealed that the redox characteristics of drugs show that the drugs with poor bioavailability generate massive outliers in the system. The drug components with little IP or EA are quite unstable and readily decomposes hence lowers the lifespan of the drugs. Throughout the investigation, administration of compounds occurred closer to the surface.  In most cases, the bio-active compounds comply with the unstrained conditions where the theoretically active molecular descriptor offers different models to the developer. [8]

The process of mapping out the related drugs for optimal usage is quite vital in the making.  Abrupt elimination of medicines after effective analysis and presentation of drug characteristics, similarly, the knowledge of drug cardiogenetic liability sustains the overall performance of prodrugs in the system.  The investigation of adopted prodrug compounds with distinct molecular entities that complied with clinical trials constitutes physiologically active drugs approved in the improvement of several lives in the pharmaceutical field. The comparative matrices provide classical analytical tools used to generate accurate relative solutions that help the clinicians in making a relevant decision regarding drugs intended for use by the majority in the improvement of health status. [13]

In the research conducted regarding product calculation based on the DFT, ideas and strategies adopted to define the link and chemical space that validate the boundaries of the public domain.  The existence of both carcinogens and halogens within screening and collection points affects the designated area of chemical space. [6]


Fig Absorption difference spectra of radicals [7]

The determination of one-electron reduction potential that underwent redox reaction to an equilibrium status with a methyl viologen and a triquat presents stronger electron-donating group compared to a weaker alkyl substitution. An efficient bioreduction occurred at increased metabolization energy at the anion spectrum of 2/3 resulted from the reaction of the CO2 within the visible spectrum. The process relies on the absorption intensity that fluctuates with pH, while the decay of radical anions will comply with the first order kinetics that exhibits constant rates at low pH and decreasing rates at a steadily inclining pH value. [1]

Fig First-order decay [7]

Analysis of graph plotted at the inverse of the first half-life 1/t0 versus the 2/3 of bimolecular decay revealed a greater extent of protonated morpholine with lower pK compared to the unreduced compounds. The existence of first-order kinetic desirable for back oxidation meant for radical anions within molecular oxygen resulted from the decay product of the transient saturated solution. The intercept of graph presents the constant rate linked to the first order reaction that corresponds to the value of k. Dehydrated protonated anion forms oxidizing benzodiazinyl radicals with either one electron oxidation or two electrons reduced metabolite. [17]

DFT Calculations

The DFT calculation involves geometric optimization based on the Gaussian energy data projected by the selected analytical software for the unrestrictedDFT. The presence of zero point vibrational energies (ZPE) complied with the Wong (0.9804)56 scale. Calculation of relative charges for protonated radical anions follows the three principle elimination pathways that are the 3-4, 3-5, 3-6 resulting in OH and aryl radical, indicating the likely process of water elimination from the anion protonated reactions that is moderately endothermic. Calculations revealed several imaginary frequencies depicting the presence of low potential energy on the surface. The preceding calculations of available energy followed the 6-311 + G (2df, p) formula. The entire process of energy, determination relied on water simulation at polarized continuum models the applicable morpholine moiety protonation occurred at the distal nitrogen intended for solvent simulation purposes.  Calculation of reaction steps involved subtraction of the ZPE energies of reactants from that of the principle products. [5]


The resulting physiochemical characteristic, generated through the DFT identified the prodrug utility as a molecular descriptor in the pharmaceutical settings. The harmonization of both theoretical and experimental data provided the prediction power for the entire branching. Calculated DFT energies altered the effec6t of mitomycin compounds as the hypothetical may highly affect or predict the progress of one and two electron reduction mitomycin bonding. Adoption of the intensive theoretical approach of prodrug analysis omits the influence of adduct DNA role in drug formulation. Accurate prediction of experimental observations of statistical variables provides comprehensive coverage bioreductive components of alkynes. The one electron reduction generates oxygen sensitive radical anion that is quite an unstable form of oxidizing radicals. In the case of carbon-centered radicals exhibit stable oxidizing characteristics the facilitate cytotoxicity in the bioreductive compounds that make the DNA double strand to disintegrate.

The overall performance of calculated DFT encountered different categories of error that drifted the degree of accuracy.  Furthermore, research into the performance of redox potential on the oxidation and reduction of prodrug development need to precisely consider the objective experimental variables as they have a direct influence on the outcome and performance of other enzymes. Compounds with less complex chains undergo rapid dissociation and electron transfer, and the resultant energy becomes compatible with Marcus theory. Such methods simply provide a leeway for the explanation of the kinetic instead of depicting real physical reactions that occur. The need for improved performance of an active component of drugs advances drug apathy and disease tolerance have increased the level at which prodrug development takes place, the research conducted in the clinical environment through experimental and theoretical data comparison yielded adequate proof relating the performance of prodrug production and use in the pharmaceutical field. The research paper revealed the probable of drug improvement in the pharmaceutical industry as well as the clinical application environments


Works Cited

[1] J. Butler and B. Hoey, “The one-electron reduction potential of several substrates can be related to their reduction rates by cytochrome P-450 reductase”, Biochimica et Biophysica Acta (BBA) – Protein Structure and Molecular Enzymology, 1993, vol. 1161, no. 1, pp. 73-78.

[2] P. Hume, M. Brimble and J. Reynisson, “The Bioreductive Alkylation of DNA by Kalafungin: A Theoretical Investigation”, Aust. J. Chem., 2007.

[3] P. Hume, M. Brimble and J. Reynisson, “DNA adduct formation of mitomycin C. A test case for DFT calculations on model systems”, Computational and Theoretical Chemistry, 2013, vol. 1005, pp. 9-15.

[4] G. Maroulis, “Evaluating the performance of DFT methods in electric property calculations: sodium chloride as a test case”, RTC, 2013, p. 1.

[5] D. Xenides, “On the performance of DFT methods in (hyper)polarizability calculations: N4 (Td) as a test case”, Journal of Molecular Structure: THEOCHEM, 2007, vol. 804, no. 1-3, pp. 41-46.

[6] K. Drew and J. Reynisson, “The impact of carbon–hydrogen bond dissociation energies on the prediction of the cytochrome P450 mediated major metabolic site of drug-like compounds”, European Journal of Medicinal Chemistry, 2012, vol. 56, pp. 48-55.

[7] P. Rydberg, P. Vasanthanathan, C. Oostenbrink and L. Olsen, “Fast Prediction of Cytochrome P450 Mediated Drug Metabolism”, ChemMedChem, 2009, vol. 4, no. 12, pp. 2070-2079.

[8] J. Zhao, S. Guan, X. Zhou, W. Han, B. Cui, and Y. Chen, “ChemInform Abstract: Bioreduction of the C=C Double Bond with Pseudomonas monteilii ZMU-T17: One Approach to 3-Monosubstituted Oxindoles.”, ChemInform, 2016, vol. 47, no. 38.

[9] P. Yadav, A. Marshall, J. Reynisson, W. Denny, M. Hay and R. Anderson, “Fragmentation of the quinoxaline N-oxide bond to the ˙OH radical upon one-electron bioreduction”, Chem. Commun., 2014, vol. 50, no. 89, pp. 13729-13731.

[10] J. Rautio, H. Kumpulainen, T. Heimbach, R. Oliyai, D. Oh, T. Järvinen and J. Savolainen, “Prodrugs: design and clinical applications”, Nature Reviews Drug Discovery, 2008, vol. 7, no. 3, pp. 255-270.

[11] U. Zeymer, R. Dechend, E. Deeg, E. Kaiser, J. Senges, D. Pittrow and R. Schmieder, “Aliskiren for the treatment of essential hypertension under real-life practice conditions: design and baseline data of the prospective 3A registry”, International Journal of Clinical Practice, 2012, vol. 66, no. 3, pp. 251-261.

[12] S. Ameta, J. Becker and A. Jäschke, “RNA–peptide conjugate synthesis by inverse-electron-demand Diels–Alder reaction”, Organic & Biomolecular Chemistry, 2014, vol. 12, no. 26, p. 4701.

[13] X. Zhu and S. Chiba, “TEMPO-mediated allylic C–H amination with hydrazones”, Organic & Biomolecular Chemistry, 2014, vol. 12, no. 26, p. 4567.

[14] R. Anderson, P. Yadav, D. Patel, J. Reynisson, S. Tipparaju, C. Guise, A. Patterson, W. Denny, A. Maroz, S. Shinde and M. Hay, “Characterisation of radicals formed by the triazine 1,4-dioxide hypoxia-activated prodrug, SN30000”, Org. Biomol. Chem., 2014, vol. 12, no. 21, pp. 3386-3392.

[15] J. Hue “Correction: Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-Activated Prodrug TH-302, In Vivo and In Vitro”, Molecular Cancer Therapeutics, 2013, vol. 14, no. 7, pp. 1762-1762.

[16] I. Lohse, J. Rasowski, P. Cao, M. Pintilie, T. Do, M. Tsao, R. Hill and D. Hedley, “Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302”, Oncotarget, 2014.

[17] S. Simtchouk, J. Eng, C. Meints, C. Makins and K. Wolthers, “Kinetic analysis of cytochrome P450 reductase from Artemisia annua reveals accelerated rates of NADPH-dependent flavin reduction”, FEBS J, 2013, vol. 280, no. 24, pp. 6627-6642.