ABSTRACT
Disentangling inputs of aeolian dust, ice-rafted debris (IRD), and eroded continental detritus delivered by ocean currents to marine sediments provide important insights into Earth System processes and climate. This study uses Sr-Nd-Pb isotope ratios of the continent-derived (lithogenic) fraction in deep-sea core TN057-6 from the subantarctic Southern Ocean southwest of Africa over the past 150,000 y to identify source regions and quantify their relative contributions and fluxes utilizing a mixing model set in a Bayesian framework. The data are compared with proxies from parallel core Ocean Drilling Program Site 1090 and newly presented data from potential South America aeolian dust source areas (PSAs), allowing for an integrated investigation into atmospheric, oceanic, and cryospheric dynamics. PSA inputs varied on glacial/interglacial timescales, with southern South American sources dominating up to 88% of the lithogenic fraction (mainly Patagonia, which provided up to 68%) during cold periods, while southern African sources were more important during interglacials. During the warmer Marine Isotope Stage (MIS) 3 of the last glacial period, lithogenic fluxes were twice that of colder MIS2 and MIS4 at times, and showed unique isotope ratios best explained by Antarctic-derived IRD, likely from the Weddell Sea. The IRD intrusions contributed up to 41% at times and followed Antarctic millennial warming events that raised temperatures, causing instability of icesheet margins. High IRD was synchronous with increased bioavailable iron, nutrient utilization, high biological productivity, and decreased atmospheric CO2. Overall, TN057-6 sediments record systematic Southern Hemisphere climate shifts and cryospheric changes that impacted biogeochemical cycling on both glacial/interglacial and subglacial timescales.
ABSTRACT
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 inâ 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.
ABSTRACT
The migration of an electron-loss center (hole) in calf thymus DNA to bisbenzimidazole ligands bound in the minor groove is followed by pulse radiolysis combined with time-resolved spectrophotometry. The initially observed absorption spectrum upon oxidation of DNA by the selenite radical is consistent with spin on cytosine (C), as the GC⢠pair neutral radical, followed by the spectra of oxidized ligands. The rate of oxidation of bound ligands increased with an increase in the ratio (r) ligands per base pair from 0.005 to 0.04. Both the rate of ligand oxidation and the estimated range of hole transfer (up to 30 DNA base pairs) decrease with the decrease in one-electron reduction potential between the GC⢠pair neutral radical of ca. 1.54 V and that of the ligand radicals (E0', 0.90-0.99 V). Linear plots of log of the rate of hole transfer versus r give a common intercept at r = 0 and a free energy change of 12.2 ± 0.3 kcal mol-1, ascribed to the GC⢠pair neutral radical undergoing a structural change, which is in competition to the observed hole transfer along DNA. The rate of hole transfer to the ligands at distance, R, from the GC⢠pair radical, k2, is described by the relationship k2 = k0 exp(constant/R), where k0 includes the rate constant for surmounting a small barrier.
Subject(s)
Base Pairing , DNA , DNA/chemistry , Free Radicals/chemistry , Oxidation-Reduction , Benzimidazoles/chemistry , Animals , Cattle , Ligands , Bisbenzimidazole/chemistry , DNA Repair , DNA Damage , Cytosine/chemistryABSTRACT
Poly(ADP-ribose)polymerase inhibitors (PARPi) are used for treatment of tumours with a defect in homologous recombination (HR) repair. Combination with radio- or chemotherapy could broaden their applicability but a major hurdle is enhancement of normal tissue toxicity. Development of hypoxia-activated prodrugs (HAPs) of PARPi has potential to restrict PARP inhibition to tumours thereby avoiding off-target toxicity. We have designed and synthesised phenolic derivatives of olaparib (termed phenolaparibs) and corresponding ether-linked HAPs. Phenolaparib cytotoxicity in HR-proficient and deficient cell lines was consistent with inhibition of PARP-1. Prodrugs were deactivated relative to phenolaparibs in biochemical PARP-1 inhibition assays, and cell culture. Prodrug 7 was selectively converted to phenolaparib 4 under hypoxia and demonstrated hypoxia-selective cytotoxicity, including chemosensitisation of HR-proficient cells in combination with temozolomide. This work demonstrates the feasibility of a HAP approach to PARPi for use in combination therapies.
ABSTRACT
Hypoxia in tumors results in resistance to both chemotherapy and radiotherapy treatments but affords an environment in which hypoxia-activated prodrugs (HAP) are activated upon bioreduction to release targeted cytotoxins. The benzotriazine 1,4-di-N-oxide (BTO) HAP, tirapazamine (TPZ, 1), has undergone extensive clinical evaluation in combination with radiotherapy to assist in the killing of hypoxic tumor cells. Although compound 1 did not gain approval for clinical use, it has spurred on the development of other BTOs, such as the 3-alkyl analogue, SN30000, 2. There is general agreement that the cytotoxin(s) from BTOs arise from the one-electron reduced form of the compounds. Identifying the cytotoxic radicals, and whether they play a role in the selective killing of hypoxic tumor cells, is important for continued development of the BTO class of anticancer prodrugs. In this study, nitrone spin-traps, combined with electron spin resonance, give evidence for the formation of aryl radicals from compounds 1, 2 and 3-phenyl analogues, compounds 3 and 4, which form carbon C-centered radicals. In addition, high concentrations of DEPMPO (5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide) spin-trap the â¢OH radical. The combination of spin-traps with high concentrations of DMSO and methanol also give evidence for the involvement of strongly oxidizing radicals. The failure to spin-trap methyl radicals with PBN (N-tert-butylphenylnitrone) on the bioreduction of compound 2, in the presence of DMSO, implies that free â¢OH radicals are not released from the protonated radical anions of compound 2. The spin-trapping of â¢OH radicals by high concentrations of DEPMPO, and the radical species arising from DMSO and methanol give both direct and indirect evidence for the scavenging of â¢OH radicals that are involved in an intramolecular process. Hypoxia-selective cytotoxicity is not related to the formation of aryl radicals from the BTO compounds as they are associated with high aerobic cytotoxicity.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Triazines/chemistry , Triazines/pharmacology , Cell Survival/drug effects , Electrons , Free Radicals/chemistry , HCT116 Cells , HT29 Cells , Humans , Hydroxyl Radical/chemistry , Neoplasms/drug therapy , Spin TrappingABSTRACT
Hypoxia-activated prodrugs (HAP) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. This study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacologic properties. Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods with observed parameters fulfilling requirements for oxygen-sensitive bioactivation. Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 µmol/L (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. Complete resistance to aerobic (two-electron) metabolism by aldo-keto reductase 1C3 was confirmed through gain-of-function studies while retention of hypoxic (one-electron) bioactivation by various diflavin oxidoreductases was also demonstrated. In vivo, the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 were significantly correlated with treatment response. Our results demonstrate that CP-506 selectively targets hypoxic tumor cells and has broad antitumor activity. Our data indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.
Subject(s)
Prodrugs/therapeutic use , Tumor Hypoxia/drug effects , Animals , Humans , Mice , Prodrugs/pharmacologyABSTRACT
The prevailing mid-latitude westerly winds, known as the westerlies, are a fundamental component of the climate system because they have a crucial role in driving surface ocean circulation1 and modulating air-sea heat, momentum and carbon exchange1-3. Recent work suggests that westerly wind belts are migrating polewards in response to anthropogenic forcing4,5. Reconstructing the westerlies during past warm periods such as the Pliocene epoch, in which atmospheric carbon dioxide (CO2) was about 350 to 450 parts per million6 and temperatures were about 2 to 4 degrees Celsius higher than today7, can improve our understanding of changes in the position and strength of these wind systems as the climate continues to warm. Here we show that the westerlies were weaker and more poleward during the warm Pliocene than during glacial periods after the intensification of Northern Hemisphere glaciation (iNHG), which occurred around 2.73 million years ago8. Our results, which are based on dust and export productivity reconstructions, indicate that major ice sheet development during the iNHG was accompanied by substantial increases in dust fluxes in the mid-latitude North Pacific Ocean, especially compared to those in the subarctic North Pacific. Following this shift, changes in dust and productivity largely track the glacial-interglacial cycles of the late Pliocene and early Pleistocene epochs. On the basis of this pattern, we infer that shifts in the westerlies were primarily driven by variations in Plio-Pleistocene thermal gradients and ice volume. By combining this relationship with other dust records9-11 and climate modelling results12, we find that the proposed changes in the westerlies were globally synchronous. If the Pliocene is predictive of future warming, we posit that continued poleward movement and weakening of the present-day westerlies in both hemispheres can be expected.
ABSTRACT
The long-lived radioisotopes of Th and Pa are unique tracers for quantifying rates of biogeochemical processes in the ocean. However, their generally low concentrations (sub-fg/kg for 230Th and 231Pa and pg/kg for 232Th) in seawater make them difficult to measure. Here, we present a new approach to determine 232Th and 230Th using Nobias PA-1 chelating resin following a bulk-extraction technique, and report for the first time the use of this resin to measure 231Pa concentrations. This method has high extraction efficiency (>80%) at pH of 4.4 ± 0.2 and the lowest procedural blanks reported in the literature: 1.0 ± 0.2 pg, 0.10 ± 0.03 fg, and 0.02 ± 0.01 fg for 232Th, 230Th, and 231Pa, respectively, representing 3%, 0.02%, and 0.01% of the total dissolved 232Th, 230Th, and 231Pa found in 5 L of a typical low-concentration surface seawater sample from the subtropical Pacific Ocean. The procedure yields data with high precision for all three isotopes (0.76% for 232Th, 0.89% for 230Th, and 0.96% for 231Pa, 2σ), allowing us to reliably measure Th and Pa in the oceans even at concentrations as low as those found in surface waters of the South Pacific Ocean. The accuracy of this method was confirmed by the analysis of well-characterized standard solutions (SW STD 2010-1 and SW STD 2015-1) and seawater samples collected aboard the FS Sonne (cruise SO245) during the UltraPac cruise in the South Pacific Ocean. Simultaneous and rapid extraction of 232Th, 230Th and 231Pa from seawater, as well as the high precision and accuracy of this method makes it ideal for both spatially and temporally high-resolution studies.
Subject(s)
Chelating Agents , Seawater , Isotopes , Oceans and SeasABSTRACT
Hypoxia is an adverse prognostic feature of solid cancers that may be overcome with hypoxia-activated prodrugs (HAPs). Tirapazamine (TPZ) is a HAP which has undergone extensive clinical evaluation in this context and stimulated development of optimized analogues. However the subcellular localization of the oxidoreductases responsible for mediating TPZ-dependent DNA damage remains unclear. Some studies conclude only nuclear-localized oxidoreductases can give rise to radical-mediated DNA damage and thus cytotoxicity, whereas others identify a broader role for endoplasmic reticulum and cytosolic oxidoreductases, indicating the subcellular location of TPZ radical formation is not a critical requirement for DNA damage. To explore this question in intact cells we engineered MDA-231 breast cancer cells to express the TPZ reductase human NADPH: cytochrome P450 oxidoreductase (POR) harboring various subcellular localization sequences to guide this flavoenzyme to the nucleus, endoplasmic reticulum, cytosol or inner surface of the plasma membrane. We show that all POR variants are functional, with differences in rates of metabolism reflecting enzyme expression levels rather than intracellular TPZ concentration gradients. Under anoxic conditions, POR expression in all subcellular compartments increased the sensitivity of the cells to TPZ, but with a fall in cytotoxicity per unit of metabolism (termed 'metabolic efficiency') when POR is expressed further from the nucleus. However, under aerobic conditions a much larger increase in cytotoxicity was observed when POR was directed to the nucleus, indicating very high metabolic efficiency. Consequently, nuclear metabolism results in collapse of hypoxic selectivity of TPZ, which was further magnified to the point of reversing O2 dependence (oxic > hypoxic sensitivity) by employing a DNA-affinic TPZ analogue. This aerobic hypersensitivity phenotype was partially rescued by cellular copper depletion, suggesting the possible involvement of Fenton-like chemistry in generating short-range effects mediated by the hydroxyl radical. In addition, the data suggest that under aerobic conditions reoxidation strictly limits the TPZ radical diffusion range resulting in site-specific cytotoxicity. Collectively these novel findings challenge the purported role of intra-nuclear reductases in orchestrating the hypoxia selectivity of TPZ.
Subject(s)
Antineoplastic Agents/chemistry , Hypoxia/drug therapy , NADPH-Ferrihemoprotein Reductase/genetics , Prodrugs/chemistry , Tirapazamine/chemistry , Antineoplastic Agents/pharmacology , Cell Engineering , Cell Hypoxia/drug effects , Cell Line, Tumor , Cell Membrane/drug effects , Cell Nucleus/drug effects , Cell Survival/drug effects , Copper/metabolism , DNA Damage/drug effects , DNA Damage/genetics , Humans , Models, Biological , NADPH-Ferrihemoprotein Reductase/metabolism , NADPH-Ferrihemoprotein Reductase/ultrastructure , Oxygen/metabolism , Prodrugs/metabolism , Tirapazamine/metabolismABSTRACT
Peroxiredoxin 2 (Prdx2) and other typical 2-Cys Prdxs function as homodimers in which hydrogen peroxide oxidizes each active site cysteine to a sulfenic acid which then condenses with the resolving cysteine on the alternate chain. Previous kinetic studies have considered both sites as equally reactive. Here we have studied Prdx2 using a combination of non-reducing SDS-PAGE to separate reduced monomers and dimers with one and two disulfide bonds, and stopped flow analysis of tryptophan fluorescence, to investigate whether there is cooperativity between the sites. We have observed positive cooperativity when H2O2 is added as a bolus and oxidation of the second site occurs while the first site is present as a sulfenic acid. Modelling of this reaction showed that the second site reacts 2.2 ± 0.1 times faster. In contrast, when H2O2 was generated slowly and the first active site condensed to a disulfide before the second site reacted, no cooperativity was evident. Conversion of the sulfenic acid to the disulfide showed negative cooperativity, with modelling of the exponential rise in tryptophan fluorescence yielding a rate constant of 0.75 ± 0.08 s-1 when the alternate active site was present as a sulfenic acid and 2.29 ± 0.08-fold lower when it was a disulfide. No difference in the rate of hyperoxidation at the two sites was detected. Our findings imply that oxidation of one active site affects the conformation of the second site and influences which intermediate forms of the protein are favored under different cellular conditions.
Subject(s)
Cysteine , Peroxiredoxins , Catalytic Domain , Cysteine/metabolism , Hydrogen Peroxide , Kinetics , Oxidation-Reduction , Peroxiredoxins/metabolismABSTRACT
Redox equilibrium between the low potential aniline radical cation and the guanine in the GC base pair of duplex DNA has been established using pulse radiolysis. We relate the measurement of a radical one-electron reduction potential, E0', of 1.01 ± 0.03 V to the perturbation of the GC base pair to accommodate the neutral guanyl radical in an energetically more stable 'slipped' structure. The formation of the 'slipped' structure is exothermic by -11.4 kcal mol-1 as calculated by DFT, which is inline with our experimental results.
Subject(s)
Cytosine/chemistry , DNA/chemistry , Electrons , Guanine/chemistry , Base Pairing , Oxidation-ReductionABSTRACT
The biogeochemical cycles of trace elements and their isotopes (TEIs) constitute an active area of oceanographic research due to their role as essential nutrients for marine organisms and their use as tracers of oceanographic processes. Selected TEIs also provide diagnostic information about the physical, geological, and chemical processes that supply or remove solutes in the ocean. Many of these same TEIs provide information about ocean conditions in the past, as their imprint on marine sediments can be interpreted to reflect changes in ocean circulation, biological productivity, the ocean carbon cycle, and more. Other TEIs have been introduced as the result of human activities and are considered contaminants. The development and implementation of contamination-free methods for collecting and analyzing samples for TEIs revolutionized marine chemistry, revealing trace element distributions with oceanographically consistent features and new insights about the processes regulating them. Despite these advances, the volume and geographic coverage of high-quality TEI data by the end of the twentieth century were insufficient to constrain their global biogeochemical cycles. To accelerate progress in this field of research, marine geochemists developed a coordinated international effort to systematically study the marine biogeochemical cycles of TEIs-the GEOTRACES program. Following a decade of planning and implementation, GEOTRACES launched its main field effort in 2010. This review, roughly midway through the field program, summarizes the steps involved in designing the program, its management structure, and selected findings.
Subject(s)
Environmental Monitoring/methods , Isotopes/analysis , Isotopes/metabolism , Oceanography/methods , Seawater/chemistry , Trace Elements/analysis , Trace Elements/metabolism , Atlantic Ocean , Geologic Sediments/chemistry , Oceanography/trendsABSTRACT
Gene-directed enzyme prodrug therapy (GDEPT) uses tumor-tropic vectors to deliver prodrug-converting enzymes such as nitroreductases specifically to the tumor environment. The nitroreductase NfsB from Escherichia coli (NfsB_Ec) has been a particular focal point for GDEPT and over the past 25 years has been the subject of several engineering studies seeking to improve catalysis of prodrug substrates. To facilitate clinical development, there is also a need to enable effective non-invasive imaging capabilities. SN33623, a 5-nitroimidazole analogue of 2-nitroimidazole hypoxia probe EF5, has potential for PET imaging exogenously delivered nitroreductases without generating confounding background due to tumor hypoxia. However, we show here that SN33623 is a poor substrate for NfsB_Ec. To address this, we used assay-guided sequence and structure analysis to identify two conserved residues that block SN33623 activation in NfsB_Ec and close homologues. Introduction of the rational substitutions F70A and F108Y into NfsB_Ec conferred high levels of SN33623 activity and enabled specific labeling of E. coli expressing the engineered enzyme. Serendipitously, the F70A and F108Y substitutions also substantially improved activity with the anticancer prodrug CB1954 and the 5-nitroimidazole antibiotic prodrug metronidazole, which is a potential biosafety agent for targeted ablation of nitroreductase-expressing vectors.
Subject(s)
Drug Monitoring/methods , Escherichia coli Proteins/metabolism , Etanidazole/analogs & derivatives , Hydrocarbons, Fluorinated/metabolism , Molecular Imaging/methods , Nitroimidazoles/therapeutic use , Nitroreductases/metabolism , Positron-Emission Tomography/methods , Prodrugs/therapeutic use , Antineoplastic Agents/therapeutic use , Biosensing Techniques/methods , Cell Hypoxia/physiology , Enzyme Activation , Escherichia coli/enzymology , Escherichia coli/genetics , Escherichia coli Proteins/genetics , Etanidazole/chemistry , Etanidazole/metabolism , Genetic Therapy/methods , HCT116 Cells , Humans , Hydrocarbons, Fluorinated/chemistry , Imidazoles/pharmacology , Imidazoles/therapeutic use , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Nitroimidazoles/pharmacology , Nitroreductases/genetics , Prodrugs/metabolism , Protein EngineeringABSTRACT
Extracellular acidification is an important feature of tumor microenvironments but has yet to be successfully exploited in cancer therapy. The reversal of the pH gradient across the plasma membrane in cells that regulate intracellular pH (pHi) has potential to drive the selective uptake of weak acids at low extracellular pH (pHe). Here, we investigate the dual targeting of low pHe and hypoxia, another key feature of tumor microenvironments. We prepared eight bioreductive prodrugs based on the benzotriazine di-oxide (BTO) nucleus by appending alkanoic or aminoalkanoic acid sidechains. The BTO acids showed modest selectivity for both low pHe (pH 6.5 versus 7.4, ratios 2 to 5-fold) and anoxia (ratios 2 to 8-fold) in SiHa and FaDu cell cultures. Related neutral BTOs were not selective for acidosis, but had greater cytotoxic potency and hypoxic selectivity than the BTO acids. Investigation of the uptake and metabolism of representative BTO acids confirmed enhanced uptake at low pHe, but lower intracellular concentrations than expected for passive diffusion. Further, the modulation of intracellular reductase activity and competition by the cell-excluded electron acceptor WST-1 suggests that the majority of metabolic reductions of BTO acids occur at the cell surface, compromising the engagement of the resulting free radicals with intracellular targets. Thus, the present study provides support for designing bioreductive prodrugs that exploit pH-dependent partitioning, suggesting, however, that that the approach should be applied to prodrugs with obligate intracellular activation.
Subject(s)
Cell Hypoxia/drug effects , Hydrogen-Ion Concentration , Neoplasms/metabolism , Prodrugs , Triazines/chemistry , Triazines/pharmacology , Cell Line, Tumor , Chemical Phenomena , Dose-Response Relationship, Drug , Drug Design , Humans , Models, Biological , Molecular Structure , Oxidation-Reduction/drug effects , OxidesABSTRACT
SCOPE: Blueberry polyphenols are thought to confer cardiovascular health benefits, but have limited bioavailability. They undergo extensive metabolism and their phenolic acid metabolites are likely to be the mediators of bioactivity. The effect of blueberry-derived phenolic acids on one aspect of inflammation, monocyte adhesion to vascular endothelial cells, is investigated. METHODS AND RESULTS: The major blueberry-derived phenolic acids in human plasma are identified and quantified. Three test mixtures representing compounds present at 0-4 h (Early), 4-24 h (Late), or 0-24 h (Whole) are used to investigate the effect on adhesion of monocytes to tumor necrosis factor alpha (TNFα)-activated endothelial cells. The Late mixture reduces monocyte adhesion, but there is no effect of the Early or Whole mixtures. Exclusion of syringic acid from each mixture results in inhibition of monocyte adhesion. Exposure to the phenolic acid mixtures has no effect on the endothelial surface expression of adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), or E-selectin, suggesting that other molecular mechanisms are responsible for the observed effect. CONCLUSION: This study shows that physiological concentrations of blueberry polyphenol metabolites can help maintain cardiovascular health by regulating monocyte adhesion to the vascular endothelium.
Subject(s)
Blueberry Plants/chemistry , Hydroxybenzoates/blood , Hydroxybenzoates/pharmacology , Monocytes/drug effects , Cell Adhesion/drug effects , Cell Adhesion Molecules/metabolism , Flow Cytometry , Gallic Acid/analogs & derivatives , Gallic Acid/pharmacology , Human Umbilical Vein Endothelial Cells , Humans , Hydroxybenzoates/isolation & purification , Monocytes/cytology , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Particulate organic carbon (POC) produced in the surface ocean sinks through the water column and is respired at depth, acting as a primary vector sequestering carbon in the abyssal ocean. Atmospheric carbon dioxide levels are sensitive to the length (depth) scale over which respiration converts POC back to inorganic carbon, because shallower waters exchange with the atmosphere more rapidly than deeper ones. However, estimates of this carbon regeneration length scale and its spatiotemporal variability are limited, hindering the ability to characterize its sensitivity to environmental conditions. Here, we present a zonal section of POC fluxes at high vertical and spatial resolution from the GEOTRACES GP16 transect in the eastern tropical South Pacific, based on normalization to the radiogenic thorium isotope 230Th. We find shallower carbon regeneration length scales than previous estimates for the oligotrophic South Pacific gyre, indicating less efficient carbon transfer to the deep ocean. Carbon regeneration is strongly inhibited within suboxic waters near the Peru coast. Canonical Martin curve power laws inadequately capture POC flux profiles at suboxic stations. We instead fit these profiles using an exponential function with flux preserved at depth, finding shallow regeneration but high POC sequestration below 1,000 m. Both regeneration length scales and POC flux at depth closely track the depths at which oxygen concentrations approach zero. Our findings imply that climate warming will result in reduced ocean carbon storage due to expanding oligotrophic gyres, but opposing effects on ocean carbon storage from expanding suboxic waters will require modeling and future work to disentangle.
ABSTRACT
Amide- and ester-linked kinase inhibitor-cytotoxin conjugates were rationally designed and synthesised as prototype hypoxia-activated anticancer mutual prodrugs. Chemical reduction of an aryl nitro trigger moiety was shown to initiate a spontaneous cyclisation/fragmentation reaction that simultaneously released the kinase inhibitor semaxanib (SU5416) and the amine- or alcohol-linked cytotoxin from the prodrugs. Preliminary cell testing and reduction potential measurements support optimisation of the compounds towards tumour-selective mutual prodrugs.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cytotoxins/chemistry , Prodrugs/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Alcohols/chemistry , Amines/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Cytotoxins/pharmacology , Drug Screening Assays, Antitumor/methods , Floxuridine/chemistry , Humans , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Prodrugs/pharmacology , Proof of Concept Study , Protein Kinase Inhibitors/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , Tumor HypoxiaABSTRACT
Changes in bioavailable dust-borne iron (Fe) supply to the iron-limited Southern Ocean may influence climate by modulating phytoplankton growth and CO2 fixation into organic matter that is exported to the deep ocean. The chemical form (speciation) of Fe impacts its bioavailability, and glacial weathering produces highly labile and bioavailable Fe minerals in modern dust sources. However, the speciation of dust-borne Fe reaching the iron-limited Southern Ocean on glacial-interglacial timescales is unknown, and its impact on the bioavailable iron supply over geologic time has not been quantified. Here we use X-ray absorption spectroscopy on subantarctic South Atlantic and South Pacific marine sediments to reconstruct dust-borne Fe speciation over the last glacial cycle, and determine the impact of glacial activity and glaciogenic dust sources on bioavailable Fe supply. We show that the Fe(II) content, as a percentage of total dust-borne Fe, increases from â¼5 to 10% in interglacial periods to â¼25 to 45% in glacial periods. Consequently, the highly bioavailable Fe(II) flux increases by a factor of â¼15 to 20 in glacial periods compared with the current interglacial, whereas the total Fe flux increases only by a factor of â¼3 to 5. The change in Fe speciation is dominated by primary Fe(II) silicates characteristic of glaciogenic dust. Our results suggest that glacial physical weathering increases the proportion of highly bioavailable Fe(II) in dust that reaches the subantarctic Southern Ocean in glacial periods, which represents a positive feedback between glacial activity and cold glacial temperatures.
Subject(s)
Dust/analysis , Iron/chemistry , Phytoplankton/growth & development , Atmosphere/chemistry , Carbon Dioxide/chemistry , Climate , Geologic Sediments/chemistry , Ice Cover/chemistry , Minerals/chemistry , Oceans and Seas , Seawater/chemistry , TemperatureABSTRACT
Oxidative damage is a common process in many biological systems and proteins are major targets for damage due to their high abundance and very high rate constants for reaction with many oxidants (both radicals and two-electron species). Tryptophan (Trp) residues on peptides and proteins are a major sink for a large range of biological oxidants as these side-chains have low radical reduction potentials. The resulting Trp-derived indolyl radicals (Trpâ¢) have long lifetimes in some circumstances due to their delocalized structures, and undergo only slow reaction with molecular oxygen, unlike most other biological radicals. In contrast, we have shown previously that Trp⢠undergo rapid dimerization. In the current study, we show that Trp⢠also undergo very fast reaction with superoxide radicals, O2â¢-, with k 1-2â¯×â¯109 M-1 s-1. These values do not alter dramatically with peptide structure, but the values of k correlate with overall peptide positive charge, consistent with positive electrostatic interactions. These reactions compete favourably with Trp⢠dimerization and O2 addition, indicating that this may be a major fate in some circumstances. The Trp⢠+â¯O2â¢- reactions occur primarily by addition, rather than electron transfer, with this resulting in high yields of Trp-derived hydroperoxides. Subsequent degradation of these species, both stimulated and native decay, gives rise to N-formylkynurenine, kynurenine, alcohols and diols. These data indicate that reaction of O2â¢- with Trp⢠should be considered as a major pathway to Trp degradation on peptides and proteins subjected to oxidative damage.