Nanoscale Magnetic Arrays through Block Copolymer Templating of Polyoxometalates.

Magnetic nanoarrays promise to enable new energy-efficient computations based on spintronics or magnonics. In this work, we present a block copolymer-assisted strategy for fabricating ordered magnetic nanostructures on silicon and permalloy substrates. Block copolymer micelle-like structures were used as a template in which polyoxometalate (POM) clusters could assemble in an opal-like structure. A combination of microscopy and scattering techniques was used to confirm the structural and organizational features of the fabricated materials. The magnetic properties of these materials were investigated by polarized neutron reflectometry, nuclear magnetic resonance, and magnetometry measurements. The data show that a magnetic structural design was achieved and that a thin layer of patterned POMs strongly influenced an underlying permalloy layer. This work demonstrates that the bottom-up pathway is a potentially viable method for patterning magnetic substrates on a sub-100 nm scale, toward the magnetic nanostructures needed for spintronic or magnonic crystal devices.

Masking the Bioactivity of Hydroxamic Acids by Coordination to Cobalt: Towards Bioreductive Anticancer Agents.

The clinical use of many potent anticancer agents is limited by their non-selective toxicity to healthy tissue. One of these examples is vorinostat (SAHA), a pan histone deacetylase inhibitor, which shows high cytotoxicity with limited discrimination for cancerous over healthy cells. In an attempt to improve tumor selectivity, we exploited the properties of cobalt(III) as a redox-active metal center through stabilization with cyclen and cyclam tetraazamacrocycles, masking the anticancer activity of SAHA and other hydroxamic acid derivatives to allow for the complex to reach the hypoxic microenvironment of the tumor. Biological assays demonstrated the desired low in vitro anticancer activity of the complexes, suggesting effective masking of the activity of SAHA. Once in the tumor, the bioactive moiety may be released through the reduction of the CoIII center. Investigations revealed long-term stability of the complexes, with cyclic voltammetry and chemical reduction experiments supporting the design hypothesis of SAHA release through the reduction of the CoIII prodrug. The results highlight the potential for further developing this complex class as novel anticancer agents by masking the high cytotoxicity of a given drug, however, the cellular uptake needs to be improved.

Tetrahedral Pegs in Square Holes: Stereochemistry of Diboron Porphyrazines and Phthalocyanines.

The first examples of diboron complexes of the tetrapyrroles octaethylporphyrazine (OEPz) and 2,9,16,23-tetra-t-butyl-phthalocyanine (Pc) are reported, counterpoints to the better known monoboron tripyrroles, subporphyrazine and subphthalocyanine. Two stereochemical possibilities are observed, with cisoid-B2 OF2 (OEPz), both cisoid-B2 OPh2 (OEPz) and transoid-B2 OPh2 (OEPz), transoid-B2 OF2 (Pc) and cisoid-B2 OPh2 (Pc) having been isolated and characterised, including structure determinations for the OEPz complexes. This variation in stereochemistry, which can be extended to include the previously reported transoid-B2 OF2 (porphyrin), cisoid-[B2 OF2 (corrole)]- , and both transoid- and cisoid-B2 OF2 (calixphyrin), prompted a wider DFT study to elucidate the factors influencing the stereochemical preferences. This shows that the cisoid/transoid preference is correlated to the ease with which the macrocycle accommodates a rectangularly distorted N4 cavity.

Campestarenes: new building blocks with 5-fold symmetry.

Campestarene is a planar, shape-persistent macrocycle with 5-fold symmetry. A range of derivatives bearing peripheral functional groups suitable for generating supramolecular interactions has been designed and synthesised for potential applications in creating 2D quasicrystal molecular assemblies. The new campestarene derivatives bear ester, carboxylic acid, methoxy, bromo, 4-pyridyl, 4-cyanophenyl and 4-phenyl carboxylic acid groups, including further derivatives of the latter two bearing alkyl chains on the phenyl groups to improve solubility. The campestarene derivatives were prepared by reductive condensation of phenol precursors bearing nitro and formyl groups using Na2S2O4. The target functional groups were installed either by pre-cyclisation derivatisation or by synthesis of methoxy-substituted campestarene and subsequent derivatisation. The cyclisation reaction is tolerant of the functional groups introduced. The ten new campestarene derivatives were characterised by NMR spectroscopy and MALDI-TOF MS, although the poor solubility of some examples precluded their detailed characterisation.

Paracentral acute middle maculopathy as a finding in patients with severe vision loss following phacoemulsification cataract surgery.

IMPORTANCE: Paracentral acute middle maculopathy (PAMM) diagnosed by spectral domain optical coherence tomography (SD-OCT) in patients with poor visual outcome post cataract surgery. BACKGROUND: Case series of severe vision loss due to PAMM after cataract surgery. DESIGN: Retrospective case series. PARTICIPANTS: Cases from five surgical centres in Victoria, Australia. METHODS: Retrospective analysis of cases with unexplained 'patch-off' vision loss post cataract surgery. All patients in our cohort had PAMM and presumed diagnosis of central or transient retinal artery occlusion. MAIN OUTCOME MEASURES: A review of the patient histories focusing on pre-operative ocular and systemic vascular risk factors, anaesthetic and operative factors. RESULTS: Ten cases were included. All patients had 6/72 Snellen visual acuity or worse noted on day one post surgery. Three patients had features of central retinal artery occlusion consisting of retinal pallor with a 'cherry red' macula but absent relative afferent pupillary defect. Seven had no features of retinal pallor or attenuation of retinal arterioles. On SD-OCT, all eyes had evident PAMM. Six patients had a history of cardiovascular disease or blood dyscrasia. CONCLUSIONS AND RELEVANCE: PAMM should be considered in patients with 'patch off' visual loss and absence of other fundal signs. We hypothesise that spasm or transient occlusion of central retinal artery leads to arterial hypoperfusion with subsequent ischaemia or infarction of the retina. Underlying arterial disease may have led to pre-existing hypoperfusion that may have been further compromised by raised intraocular pressure during the procedure itself or via raised orbital pressure from the anaesthesia.

Lighting up sugars: fluorescent BODIPY-gluco-furanose and -septanose conjugates linked by direct B-O-C bonds.

We report the first O-BODIPY-glucose conjugates, in which the sugar is directly attached to the BODIPY boron through covalent B-O-C bonds. The reaction of Cl-BODIPY with glucose in acetonitrile produced the 1 : 1 α-glucofuranose BODIPY (1), 1 : 2 α-glucofuranose BODIPY (2) and 1 : 2 α-glucoseptanose BODIPY (3) esters. Compound 3 is a rare instance of the unnatural septanose form of glucose, and the first example of a septanose borate.

Cross-bridged cyclen or cyclam Co(III) complexes containing cytotoxic ligands as hypoxia-activated prodrugs.

A series of cobalt(III) complexes of the potent DNA minor groove alkylator (1-(chloromethyl)-5-hydroxy-1H-pyrrolo[3,2-f]quinolin-3(2H)-yl)(5,6,7-trimethoxy-1H-indol-2-yl)methanone (3; seco-CPyI-TMI), with cyclam or cyclen auxiliary ligands (L3 and L5) containing a cross-bridging ethylene (CH2CH2) group or the N,N'-dimethyl derivatives of these (L4 and L6), was prepared. Two 8-quinolinato (2) model complexes of these, [Co(L3)(2)](ClO4)2 and [Co(L6)(2)](ClO4)2, and the aquated derivative [Co(L6)(H2O)2](OTf)3 were characterized by X-ray crystallography. Electrochemistry of the 8-quinolinato model complexes showed that the Co(III)/(II) reduction potential was lowered relative to the unsubstituted cyclen ligand. Evaluation of the cytotoxicity of the racemic seco-CPyI cobalt complexes in vitro showed considerable attenuation of their cytotoxicity relative to the free alkylator and marked hypoxic selectivity, especially [Co(L3)(3)](2+) (9), which was 81-212-fold more potent under hypoxia than 20% oxygen in a panel of 10 human tumor cell lines. However, 9 did not elicit significant killing of hypoxic cells in HT29 tumor xenografts, suggesting possible pharmacological limitations in vivo.

Modeling left ventricular diastolic dysfunction: classification and key indicators.

BACKGROUND: Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported. METHODS: We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations. RESULTS: IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O2 and CO2 differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD. CONCLUSION: The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease.

N-alkylated cyclen cobalt(III) complexes of 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol DNA alkylating agent as hypoxia-activated prodrugs.

A series of cobalt complexes of the potent DNA minor groove alkylator 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol (seco-6-azaCBI-TMI) were prepared from a series of N-substituted cyclen ligands. The final N-substituted complexes carried formal overall charges ranging from +2 to -2 and showed limited improvements in solubility. They showed similar stabilities to that of the complex with the unsubstituted cyclen ligand, and large but variable attenuation of the cytotoxicity of the free alkylator (2-30-fold), compared to 150-fold for the unsubstituted ligand. However, they had oxic/hypoxic ratios (2-22-fold) comparable to that of the unsubstituted cyclen complex (5).

Macrocyclic pentamers functionalised around their periphery as potential building blocks.

The elaboration of a five-fold symmetric macrocyclic aromatic pentamer bearing peripheral benzyloxy and hydroxyl groups is described. These could be used to explore further functionalisation for use as pentagonal building blocks. The internal fluorine-substituted macrocycle has been prepared via a one-pot procedure which is an improvement on the stepwise chain growth approach reported in the literature.

Synthetic routes to mixed-ligand cobalt(III) dithiocarbamato complexes containing imidazole, amine and pyridine donors and the X-ray crystal structure of a cobalt(III) bis(dithiocarbamato) histamine complex.

The binuclear cobalt complex [Co(2)(Me(2)dtc)(5)](+) reacts with a range of nitrogen donor ligands L' or L'' to form an equimolar mixture of Co(Me(2)dtc)(3) and the mixed-ligand complexes [Co(Me(2)dtc)(2)(L')(2)](+) or [Co(Me(2)dtc)(2)(L'')](+), where (L')(2) is two monodentate ligands and (L'') is one bidentate ligand. The complexes prepared by this route contain the monodentate ligands L'=1-methyl-imidazole, 1-methyl-5-nitro-imidazole and benzimidazole, all of which coordinate to cobalt through an imidazole nitrogen atom. Symmetrical bidentate ligand complexes contain the bisimidazole L''=2,2'-bis(4,5-dimethylimidazole), the diamine L''=1,2-diaminobenzene and the pyridine donors L''=2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine and 1,10-phenanthroline. Two examples of complexes with unsymmetrical bidentate imidazole-amine donors were prepared in which L''=4-(2-aminoethyl)imidazole (histamine) and 2-aminomethylbenzimidazole. All new complexes were fully characterised, and the X-ray crystal structure of the histamine complex [Co(Me(2)dtc)(2)(hist)]ClO(4) is also reported.

Pulse radiolysis investigation on the mechanism of the catalytic action of Mn(II)-pentaazamacrocycle compounds as superoxide dismutase mimetics.

The mechanism for the catalytic dismutation of superoxide by the Mn(II) pentaazamacrocyclic compound M40403 ([manganese(II) dichloro-(4 R,9 R,14 R,19 R)-3,10,13,20,26 pentaazatetracyclo [20.3.1.0 (4,9).0 (14,9)] hexacosa-1(26),-22(23),24-triene], SODm1) and two 2,21-dimethyl analogues has been investigated using pulse radiolysis. The initial rate of reaction between superoxide and the manganese compounds was found to be dependent on structure and pH, with the resulting transient adducts possessing spectral characteristics of the metal center being oxidized to Mn(III). Values for the p K a of the transient adducts (p K a = 5.65 +/- 0.05; 5.3 +/- 0.1 and <5 for SODm1, SODm2 and SODm3, respectively) were obtained from spectrophotometric and conductivity measurements. Reaction of these transient adducts with further superoxide was highly structure dependent with the 2 S,21 S-dimethyl derivative (SODm2) being highly catalytically active at pH 7.4 ( k cat = 2.35 x 10 (8) M (-1) s (-1)) compared to SODm1 ( k cat = 3.55 x 10 (6) M (-1) s (-1)). In contrast the 2 R,21 R-dimethyl derivative (SODm3) showed no dismutation catalysis at all. The reaction rates of the initial complexes with HO 2 (*) were significantly lower than with O 2 (*-), and it is proposed that O 2 (*-) is the main reactant in the catalytic cycle at pH 7.4. Variable temperature studies revealed major differences in the thermodynamics of the catalytic cycles involving SODm2 or SODm1. In the case of SODm2, the observed high entropic contribution to the activation energy is indicative of ligand conformational changes during the catalytic step. These results have provided the basis for a new mechanism for the catalytic dismutation of superoxide by Mn(II)-pentaazamacrocycle SOD mimetics.

Boron calixphyrin complexes: exploring the coordination chemistry of a BODIPY/porphyrin hybrid.

Boron complexes of calix[4]phyrins (1.1.1.1) were prepared by reacting the free-base ligands with BF3·Et2O. The reaction conditions can be efficiently tailored to produce mono- or di-boron calixphyrins. Mono-BF2 calixphyrins with boron coordinating to either the dipyrrin, BF2[H(Calix)], or dipyrromethane, BF2[H(Calix)] and BF2[H2(Calix)]+, bonding sites were isolated. The dipyrromethane isomer, BF2[H(Calix)], isomerises into BF2[H(Calix)] which kinetic studies and DFT calculations indicate is an intramolecular process. Two isomers of B2OF2(Calix) were isolated, one isomer bonding via the dipyrrin sites with the FBOBF moiety in cisoid geometry, and the second isomer bonding via the dipyrromethane sites with the FBOBF moiety in transoid geometry. Although the cisoid/dipyrrin isomer was calculated to be most energetically favourable for B2OF2(Calix), the isolation of the transoid/dipyrromethane isomer is postulated to occur via the presumed intermediate (BF2)2(Calix), for which DFT indicated a preference for transoid/dipyrromethane geometry.

Syncope, seizure, or both? An unusual case of complete heart block.

Syncope and epileptic seizures have common presenting features that make it difficult to determine if a patient's collapse is primarily cardiac or neurologic. The distinction is blurred further if epileptic neural activity provokes cardiac arrhythmias known to cause syncope. We present a case of convulsive movements, progressive atrioventricular block, and syncope in a patient known to have epilepsy. The history, serial electrocardiographic tracings, and other diagnostic tests strongly suggest the ictal bradycardia syndrome. The case illustrates interesting aspects of central autonomic function and the diagnostic and therapeutic dilemmas of evaluating and treating patients who present with this problem.

Radiolytic and cellular reduction of a novel hypoxia-activated cobalt(III) prodrug of a chloromethylbenzindoline DNA minor groove alkylator.

Metabolic reduction can be used to activate prodrugs in hypoxic regions of tumours, but reduction by ionising radiation is also theoretically attractive. Previously, we showed that a cobalt(III) complex containing 8-hydroxyquinoline (8-HQ) and cyclen ligands releases 8-HQ efficiently on irradiation in hypoxic solutions [Ahn G-O, Ware DC, Denny WA, Wilson WR. Optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs. Radiat Res 2004;162:315-25]. Here we investigate an analogous Co(III) complex containing the potent DNA minor groove alkylator azachloromethylbenzindoline (azaCBI, 1) to determine whether it releases 1 on radiolytic and/or enzymatic reduction under hypoxia. Monitoring by HPLC, the azaCBI ligand in the Co(III)(cyclen)(azaCBI) complex (2) slowly hydrolysed in aqueous solution, in contrast to the free ligand 1 which readily converted to its reactive cyclopropyl form. Irradiation of 2 (30-50 microM) in hypoxic solutions released 1 with yields of 0.57 micromol/J in formate buffer and 0.13 micromol/J in human plasma. Using bioassay methods, cytotoxic activation by irradiation of 2 at 1 microM in hypoxic plasma was readily detectable at clinically relevant doses (> or = 1 Gy), with a estimated yield of 1 of 0.075 micromol/J. Release of 1 from 2 was also observed in hypoxic HT29 cultures without radiation, with subsequent conversion of 1 to its O-glucuronide. Surprisingly, overexpression of human cytochrome P450 reductase in A549 cells did not increase the rate of metabolic reduction of 2, suggesting that other reductases and/or non-enzymatic reductants are responsible. Thus the cobalt(III) complex 2 is a promising prodrug capable of being activated to release a very potent cytotoxin when reduced by either ionising radiation or cells under hypoxic conditions.

Medical qualification of a commercial spaceflight participant: not your average astronaut.

BACKGROUND: Candidates for commercial spaceflight may be older than the typical astronaut and more likely to have medical problems that place them at risk during flight. Since the effects of microgravity on many medical conditions are unknown, physicians have little guidance when evaluating and certifying commercial spaceflight participants. This dynamic new era in space exploration may provide important data for evaluating medical conditions, creating appropriate medical standards, and optimizing treatment alternatives for long-duration spaceflight. CASE: A 57-yr-old spaceflight participant for an ISS mission presented with medical conditions that included moderately severe bullous emphysema, previous spontaneous pneumothorax with talc pleurodesis, a lung parenchymal mass, and ventricular and atrial ectopy. The medical evaluation required for certification was extensive and included medical studies and monitoring conducted in analogue spaceflight environments including altitude chambers, high altitude mixed-gas simulation, zero-G aircraft, and high-G centrifuge. To prevent recurrence of pneumothorax, we performed video-assisted thoracoscopic pleurodesis, and to assess lung masses, several percutaneous or direct biopsies. The candidate's 10-d mission was without incident. CONCLUSION: Non-career astronauts applying for commercial suborbital and orbital spaceflight will, at least in the near future, challenge aerospace physicians with unknowns regarding safety during training and flight, and highlight important ethical and risk-assessment problems. The information obtained from this new group of space travelers will provide important data for the evaluation and in-flight treatment of medical problems that space programs have not yet addressed systematically, and may improve the medical preparedness of exploration-class missions.

Benefits, unresolved questions, and technical issues of cardiac resynchronization therapy for heart failure.

This review aims to provide a synthesis of the published evidence regarding the rationale and clinical benefits of cardiac resynchronization therapy (CRT) with implantable atrial-synchronized biventricular pacing (BVP) devices in patients with moderate to advanced heart failure and intra- and interventricular conduction delays. In addition, it addresses clinical and technical issues that have yet to be resolved, such as the selection of the most suitable candidates for CRT; the usefulness of combining BVP with automatic defibrillation backup; the value of CRT in patients with atrial fibrillation; the importance of alternative sites of pacing, such as the atrial septum and the right ventricular (RV) outflow tract; the harmful effects of the long-standing practice of producing an iatrogenic left bundle branch block by conventional RV pacing in patients receiving standard permanent pacemakers; the question of precisely where on the left ventricle optimal pacing is achieved; and the potential applications of CRT in patients with pediatric or congenital heart disease. Considering how major advances have been achieved since the first clinical application of CRT in 1994, one can be optimistic about the future of the electrotherapeutic management of heart failure.

Reperfusion-related polymorphic ventricular tachycardia as a possible mechanism of sudden death in patients with anomalous coronary arteries.

We describe a patient with anomalous origin of the left coronary artery in whom polymorphic ventricular tachycardia developed immediately after an episode of chest pain with ST segment elevation. This is the first report providing direct evidence that reperfusion arrhythmias may be the cause of sudden death in individuals with anomalous coronary arteries.

Evaluation of the dopamine ß-hydroxylase (DßH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

In the present study, we tested the hypothesis that the potent and selective dopamine-ß-hydroxylase (DßH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.

Optimization of the auxiliary ligand shell of Cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs.

A potential approach for activating prodrugs in hypoxic regions of tumors is to use ionizing radiation, rather than bioreductive enzymes, to effect reduction. This study investigates radiolytic release of 8-hydroxyquinoline (8-HQ), as a model for hydroxyaza-chloromethylbenzindoline DNA minor groove alkylators, from Co(III) complexes under hypoxia. 8-HQ release, measured by HPLC, showed higher efficiency (one-electron stoichiometry) when the auxiliary ligand was a tetraazamacrocycle [e.g. 1,4,7,10-tetraazacyclododecane (cyclen)] rather than a triazamacrocycle [1,4,7-triazacyclononane (TACN)]. These complexes differ from the bioreductive cobalt complex SN 24771 in that their reduction provides stable cobalt-containing products rather than free (aquated) Co(2+). Radiolytic release of 8-HQ from Co(cyclen)(8-HQ) and Co(TACN)(CN)(8-HQ) was also demonstrated in deoxygenated human plasma, selectively in the absence of oxygen, again with higher efficiency for the cyclen system. The cobalt complexes were >1000-fold less potent than free 8-HQ as inhibitors of cell proliferation and were metabolically stable in aerobic and hypoxic cell cultures. Investigation of cell uptake of total cobalt, by inductively coupled plasma mass spectrometry, showed that these complexes enter cells but do not accumulate to the high concentrations seen with SN 24771. The results demonstrate the feasibility of masking the cytotoxicity of hydroxyquinoline-based cytotoxins as Co(III) complexes and demonstrate the utility of cyclen-based auxiliary ligands for optimizing radiolytic activation of these novel prodrugs under hypoxia.