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The progression of Parkinson's disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20-89 years; 33% female) and 885 controls (age: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen's d effect sizes reached d = -1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.
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In recent years, the electronic structures of organocuprates in general and the complex [Cu(CF3)4]- in particular have attracted significant interest. A possible key indicator in this context is the reactivity of these species. Nonetheless, this aspect has received only limited attention. Here, we systematically study the series of tetra-alkyl cuprates [MenCu(CF3)4-n]- and their unimolecular reactivity in the gas phase, which includes concerted formal reductive eliminations as well as radical losses. Through computational studies, we characterize the electronic structures of the complexes and show how these are connected to their reactivity. We find that all [MenCu(CF3)4-n]- ions feature inverted ligand fields and that the distinct reactivity patterns of the individual complexes arise from the interplay of different effects.
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The oxidation state ( OS ) formalism is a much-appreciated good in chemistry, receiving wide application. However, like all formalisms, limitations are inescapable, some of which have been recently explored. Providing a broader context, we discuss the OS and its interpretation from a computational perspective for transition metal (TM) complexes. We define a broadly applicable and easy-to-use procedure to derive OS s based on quantum chemical calculations, via the use of localized orbitals, dubbed the Intrinsic OS . Applying this approach to a cobalt complex in five OS s, isolated by Hunter and co-workers (Inorg. Chem.2021, 60, 17445), we find that the calculated Intrinsic OS matches the formal OS , consistent with the experimental characterization. Through analysis of the delocalized orbitals, the ligand field of the Co(III) complex is found to be "inverted", despite every cobalt-ligand bond being classically dative from the localized perspective-a bonding scenario very similar to that of [Cu(CF3)4]-. This is not atypical but rather a natural consequence of these metals bonding in the high-valent region, and we propose a more restrictive definition of (locally) inverted bonding. Additionally, two bonding descriptors within the Intrinsic Bonding Orbital (IBO) framework (σ-gain and π-loss) are introduced, which enable facile quantification of electron-sharing covalency across a broad range of TM complexes.
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OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.
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Dopamina , Enfermedad por Cuerpos de Lewy , Aprendizaje Automático , Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Sinucleinopatías , Humanos , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Masculino , Femenino , Anciano , Sinucleinopatías/diagnóstico por imagen , Persona de Mediana Edad , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/complicaciones , Dopamina/metabolismo , Tomografía Computarizada de Emisión de Fotón Único , Terminales Presinápticos/metabolismo , Imágenes DopaminérgicasRESUMEN
S = 2 FeIVâO centers generated in the active sites of nonheme iron oxygenases cleave substrate C-H bonds at rates significantly faster than most known synthetic FeIVâO complexes. Unlike the majority of the latter, which are S = 1 complexes, [FeIV(O)(tris(2-quinolylmethyl)amine)(MeCN)]2+ (3) is a rare example of a synthetic S = 2 FeIVâO complex that cleaves C-H bonds 1000-fold faster than the related [FeIV(O)(tris(pyridyl-2-methyl)amine)(MeCN)]2+ complex (0). To rationalize this significant difference, a systematic comparison of properties has been carried out on 0 and 3 as well as related complexes 1 and 2 with mixed pyridine (Py)/quinoline (Q) ligation. Interestingly, 2 with a 2-Q-1-Py donor combination cleaves C-H bonds at 233 K with rates approaching those of 3, even though Mössbauer analysis reveals 2 to be S = 1 at 4 K. At 233 K however, 2 becomes S = 2, as shown by its 1H NMR spectrum. These results demonstrate a unique temperature-dependent spin-state transition from triplet to quintet in oxoiron(IV) chemistry that gives rise to the high C-H bond cleaving reactivity observed for 2.
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We report the preparation and characterization of the dinuclear AuII hydroxide complex AuII 2(L)2(OH)2 (L=N,N'-bis (2,6-dimethyl) phenylformamidinate) and study its reactivity towards weak X-H bonds. Through the interplay of kinetic analysis and computational studies, we demonstrate that the oxidation of cyclohexadiene follows a concerted proton-coupled electron transfer (cPCET) mechanism, a rare type of reactivity for Au complexes. We find that the Au-Au σ-bond undergoes polarization in the PCET event leading to an adjustment of oxidation levels for both Au centers prior to C(sp3)-H bond cleavage. We thus describe the oxidation event as a valence tautomerism-induced PCET where the basicity of one reduced Au-OH unit provides a proton acceptor and the second more oxidized Au center serves as an electron acceptor. The coordination of these events allows for unprecedented radical-type reactivity by a closed shell AuII complex.
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Huntington's and Parkinson's disease are two movement disorders representing mainly opposite states of the basal ganglia inhibitory function. Despite being an integral part of the cortico-subcortico-cortical circuitry, the subthalamic nucleus function has been studied at the level of detail required to isolate its signal only through invasive studies in Huntington's and Parkinson's disease. Here, we tested whether the subthalamic nucleus exhibited opposite functional signatures in early Huntington's and Parkinson's disease. We included both movement disorders in the same whole-brain imaging study, and leveraged ultra-high-field 7T MRI to achieve the very fine resolution needed to investigate the smallest of the basal ganglia nuclei. Eleven of the 12 Huntington's disease carriers were recruited at a premanifest stage, while 16 of the 18 Parkinson's disease patients only exhibited unilateral motor symptoms (15 were at Stage I of Hoehn and Yahr off medication). Our group comparison interaction analyses, including 24 healthy controls, revealed a differential effect of Huntington's and Parkinson's disease on the functional connectivity at rest of the subthalamic nucleus within the sensorimotor network, i.e. an opposite effect compared with their respective age-matched healthy control groups. This differential impact in the subthalamic nucleus included an area precisely corresponding to the deep brain stimulation 'sweet spot'-the area with maximum overall efficacy-in Parkinson's disease. Importantly, the severity of deviation away from controls' resting-state values in the subthalamic nucleus was associated with the severity of motor and cognitive symptoms in both diseases, despite functional connectivity going in opposite directions in each disorder. We also observed an altered, opposite impact of Huntington's and Parkinson's disease on functional connectivity within the sensorimotor cortex, once again with relevant associations with clinical symptoms. The high resolution offered by the 7T scanner has thus made it possible to explore the complex interplay between the disease effects and their contribution on the subthalamic nucleus, and sensorimotor cortex. Taken altogether, these findings reveal for the first time non-invasively in humans a differential, clinically meaningful impact of the pathophysiological process of these two movement disorders on the overall sensorimotor functional connection of the subthalamic nucleus and sensorimotor cortex.
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Isoporphyrins have recently been identified as remarkable species capable of turning the nucleophile attached to the porphyrin ring into an electrophile, thereby providing umpolung of reactivity (Inorg. Chem. 2022, 61, 8105-8111). They are generated by nucleophilic attack on an iron(III) π-dication, a class of species that has received scant attention. Here, we explore the effect of the porphyrin meso-substituent and report a iron(III) π-dication bearing the meso-tetraphenylporphyrin (TPP) ligand. We provide an extensive study of the species by UV/Vis absorption, 2 Hâ NMR, EPR, applied field Mössbauer, and resonance Raman spectroscopy. We further explore the system's highly dynamic and tunable properties and address the nature of the axial ligands as well as the conformation of the porphyrin ring. The insights presented are essential for the rational design of catalysts for the umpolung of nucleophiles. Such catalytic avenues could for example provide a novel method for electrophilic chlorinations. We further examine the importance of electronic tuning of the porphyrin by nature of the meso-substituent as a factor in catalyst design.
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The reported tetracoordinate dilithio methandiide complex from Liddle and co-workers (1) is investigated from a coordination chemistry perspective, to probe the origin of its intriguing geometry. Through the application of a variety of computational techniques, non-covalent (steric, electrostatic) interactions are found to be dominant. Further, we arrive at a bonding description which emphasizes the tricoordinate sp2 -hybridized nature of the central methandiide carbon, differing somewhat from the original proposal. Thus, 1 is distinct from other dilithio methandiides since it contains only one C-Li σ-bond, and is found to be comparable to a simple aryllithium compound, phenyllithium.
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There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.
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Degeneración Corticobasal , Enfermedades Neurodegenerativas , Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Pronóstico , Enfermedades Neurodegenerativas/diagnóstico por imagenRESUMEN
The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression.
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Atrofia de Múltiples Sistemas , Trastornos Parkinsonianos , Parálisis Supranuclear Progresiva , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/tratamiento farmacológico , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/patología , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Atrofia de Múltiples Sistemas/patología , Imagen por Resonancia Magnética , Reino UnidoRESUMEN
Several gold +I and +III complexes are investigated computationally and spectroscopically, focusing on the d-configuration and physical oxidation state of the metal center. Density functional theory calculations reveal the non-negligible electron-sharing covalent character of the metal-to-ligand σ-bonding framework. The bonding of gold(III) is shown to be isoelectronic to the formal CuIII complex [Cu(CF3 )4 ]1- , in which the metal center tries to populate its formally unoccupied 3dx2-y2 orbital via σ-bonding, leading to a reduced d10 CuI description. However, Au L3 -edge X-ray absorption spectroscopy reveals excitation into the d-orbital of the AuIII species is still possible, showing that a genuine d10 configuration is not achieved. We also find an increased electron-sharing nature of the σ-bonds in the AuI species, relative to their AgI and CuI analogues, due to the low-lying 6s orbital. We propose that gold +I and +III complexes form similar bonds with substrates, owing primarily to participation of the 5dx2-y2 or 6s orbital, respectively, in bonding, indicating why AuI and AuIII complexes often have similar reactivity.
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Idiopathic rapid eye movement sleep behaviour disorder (iRBD) has now been established as an important marker of the prodromal stage of Parkinson's disease and related synucleinopathies. However, although dopamine transporter single photon emission computed tomography (SPECT) has been used to demonstrate the presence of nigro-striatal deficit in iRBD, quantifiable correlates of this are currently lacking. Sensitivity to rewarding stimuli is reduced in some people with Parkinson's disease, potentially contributing to aspects of the neuropsychiatric phenotype in these individuals. Furthermore, a role for dopaminergic degeneration is suggested by the fact that reward insensitivity can be improved by dopaminergic medications. Patients with iRBD present a unique opportunity to study the relationship between reward sensitivity and early dopaminergic deficit in the unmedicated state. Here, we investigate whether a non-invasive, objective measure of reward sensitivity might be a marker of dopaminergic status in prodromal Parkinson's disease by comparing with SPECT/CT measurement of dopaminergic loss in the basal ganglia. Striatal dopaminergic deficits in iRBD are associated with progression to Parkinsonian disorders. Therefore, identification of a clinically measurable correlate of this degenerative process might provide a basis for the development of novel risk stratification tools. Using a recently developed incentivized eye-tracking task, we quantified reward sensitivity in a cohort of 41 patients with iRBD and compared this with data from 40 patients with Parkinson's disease and 41 healthy controls. Patients with iRBD also underwent neuroimaging with dopamine transporter SPECT/CT. Overall, reward sensitivity, indexed by pupillary response to monetary incentives, was reduced in iRBD cases compared with controls and was not significantly different to that in patients with Parkinson's disease. However, in iRBD patients with normal dopamine transporter SPECT/CT imaging, reward sensitivity was not significantly different from healthy controls. Across all iRBD cases, a positive association was observed between reward sensitivity and dopaminergic SPECT/CT signal in the putamen. These findings demonstrate a direct relationship between dopaminergic deficit and reward sensitivity in patients with iRBD and suggest that measurement of pupillary responses could be of value in models of risk stratification and disease progression in these individuals.
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Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Humanos , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Dopamina , RecompensaRESUMEN
Au is known to be fairly redox inactive (in catalysis) and bind oxygen adducts only quite weakly. It is thus rather surprising that stable Au-OH complexes can be synthesized and used as oxidants for both one- and two-electron oxidations. A charged AuIII -OH complex has been shown to cleave C-H and O-H bonds homolytically, resulting in a one-electron reduction of the metal center. Contrasting this, a neutral AuIII -OH complex performs oxygen atom transfer to phosphines, resulting in a two-electron reduction of the hydroxide proton to form a AuIII -H rather than causing a change in oxidation state of the metal. We explore the details of these two examples and draw comparisons to the more conventional reactivity exhibited by AuI -OH. Although the current scope of known Au-OH oxidation chemistry is still in its infancy, the current literature exemplifies the unique properties of Au chemistry and shows promise for future findings in the field.
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Hidróxidos , Oxidantes , Oxidación-Reducción , Hidróxidos/química , Protones , Oxígeno/químicaRESUMEN
A systematic study of protodeauration, a crucial step often found in gold catalysis, was performed using isolated vinyl gold(I) complexes. By varying substituents on gold complexes, we explore how their properties influence protodeauration. Phenols were employed as the proton source, and their substituents were also varied, providing insight through variation of their acidity. A linear Hammett correlation is identified for the series of substituted vinyl gold(I) complexes, while a nonlinear trend is found for the series of substituted phenols. Computationally, we reproduce our experimental observations and identify significant noncovalent interactions (NCIs) between the proton donor and vinyl gold(I) complexes. This finding is of particular importance for gold-catalyzed reactions as they often employ linear two-coordinate complexes where the site of the reaction is spatially remote from the ligand bound to gold. The NCIs between substrates and intermediates lead to a significant acceleration of the protodeauration step in this work, opening the door to alternative strategies in the field of gold catalysis.
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Cytochrome P450s and Galactose Oxidases exploit redox active ligands to form reactive high valent intermediates for oxidation reactions. This strategy works well for the late 3d metals where accessing high valent states is rather challenging. Herein, we report the oxidation of NiII (salen) (salen=N,N'-bis(3,5-di-tert-butyl-salicylidene)-1,2-cyclohexane-(1R,2R)-diamine) with mCPBA (meta-chloroperoxybenzoic acid) to form a fleeting NiIII bisphenoxyl diradical species, in CH3 CN and CH2 Cl2 at -40 °C. Electrochemical and spectroscopic analyses using UV/Vis, EPR, and resonance Raman spectroscopies revealed oxidation events both on the ligand and the metal centre to yield a NiIII bisphenoxyl diradical species. DFT calculations found the electronic structure of the ligand and the d-configuration of the metal center to be consistent with a NiIII bisphenoxyl diradical species. This three electron oxidized species can perform hydrogen atom abstraction and oxygen atom transfer reactions.
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Galactosa , Níquel , Clorobenzoatos , Ciclohexanos , Citocromos , Diaminas , Etilenodiaminas , Galactosa Oxidasa , Hidrógeno , Ligandos , Metales , Níquel/química , Oxidación-Reducción , OxígenoRESUMEN
Nucleophilic formal gold(-I) and gold(I) complexes are investigated via Intrinsic Bond Orbital analysis and Energy Decomposition Analysis, based on density functional theory calculations. The results indicate gold(0) centres engaging in electron-sharing bonding with Al- and B- based ligands. Multiconfigurational (CASSCF) calculations corroborate the findings, highlighting the gap between the electonic structures and the oxidation state formalism.
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OBJECTIVES: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. METHODS: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer's disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. RESULTS: A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (<5×10e-8) although four variants require further follow-up, meeting a threshold of <1×10e-6. CONCLUSIONS: We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.
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Control of the spin state of metal complexes is important because it leads to a precise control over the physical properties and the chemical reactivity of the metal complexes. Currently, controlling the spin state in metal complexes is challenging because a precise control of the properties of the secondary coordination sphere is often difficult. It has been shown that non-covalent interactions in the secondary coordination sphere of transition metal complexes can enable spin state control. Here we exploit this strategy for fluorinated triazole ligands and present mononuclear CoII and FeII complexes with "click"-derived tripodal ligands that contain mono-fluorinated benzyl substituents on the backbone. Structural characterization of 1 and 2 at 100 K revealed Co-N bond lengths that are typical of high spin (HS) CoII complexes. In contrast, the Fe-N bond lengths for 3 are characteristic of a low spin (LS) FeII state. All complexes show an intramolecular face-to-face non-covalent interaction between two arms of the ligand. The influence of the substituents and of their geometric structure on the spin state of the metal center was investigated through SQUID magnetometry, which revealed spin crossover occurring in compounds 1 and 3. EPR spectroscopy sheds further light on the electronic structures of 1 and 2 in their low- and high-spin states. Quantum-chemical calculations of the fluorobenzene molecule were performed to obtain insight into the influence of fluorine-specific interactions. Interestingly, this work shows that the same fluorinated tripodal ligands induce SCO behavior in both FeII and CoII complexes.
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Recent desires to develop environmentally benign procedures for electrophilic chlorinations have encouraged researchers to take inspiration from nature. In particular, the enzyme chloroperoxidase (CPO), which is capable of electrophilic chlorinations through the umpolung of chloride by oxidation with hydrogen peroxide (H2O2), has received lots of attention. CPO itself is unsuitable for industrial use because of its tendency to decompose in the presence of excess H2O2. Biomimetic complexes (CPO active-site mimics) were then developed and have been shown to successfully catalyze electrophilic chlorinations but are too synthetically demanding to be economically viable. Reported efforts at generating the putative active chlorinating agent of CPO (an iron hypochlorite species) via the umpolung of chloride and using simple meso-substituted iron porphyrins were unsuccessful. Instead, a meso-chloroisoporphyrin intermediate was formed, which was shown to be equally capable of performing electrophilic chlorinations. The current developments toward a potential method involving this novel intermediate for environmentally benign electrophilic chlorinations are discussed. Although this novel pathway no longer follows the mechanism of CPO, it was developed from efforts to replicate its function, showing the power that drawing inspiration from nature can have.