Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101).

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

Kimura Disease in an Adult Indian Female, A Rare Presentation: A Novel Treatment with a Review of Literature.

Kimura disease (KD) is a chronic inflammatory disorder, which is quite rare and has an unclear and much debated etiology. KD is characterized by painless, nodular, subcutaneous swellings along with lymphadenopathy, encountered in the head and neck region more often. It is also known to affect major salivary glands. It is also associated with elevated Immunoglobulins (IgE) and peripheral blood and tissue eosinophilia. Kimura disease generally affects young Asian males. There is considerable difficulty in arriving at clinical diagnosis and often it is frustrating to both patients and the treating physicians because of the difficulty in its management. We are presenting and reporting a case of Kimura disease in a young adult Indian female patient who presented with a swelling in the left parotid region. We have successfully managed this patient medically with a unique combination of drugs, most of which have already been tried and reported in literature by various authors.

Youth focused life skills training and counselling services program-An inter-sectoral initiative in India: Program development and preliminary analysis of factors affecting life skills.

OBJECTIVES: This paper describes the methodology of developing and implementation of a youth focused life skills training and counselling services programme (LSTCP) and assessment of factors associated with life skills of participants pre-training. DESIGN: Development of all aspects of LSTCP (modules, methods and evaluation) was through a consultative process. Experiential learning based facilitation was decided as the approach for training participants. A quasi-experimental design with pre, post and follow-up assessment post-training was finalised. Data collection was done using specifically developed semi-structured self-administered questionnaire. RESULTS: Multivariable logistic regression with life skills as outcome and various exposure variables was performed. About 2/3rd of participants had high level of life skills (68%). Increased score of extraversion (AOR = 1.57,95% CI = 1.32-1.85), agreeableness (AOR = 1.42,95% CI = 1.16-1.73), conscientiousness (AOR = 1.9,95% CI = 1.55-2.33), physical (AOR = 1.03,95% CI = 1.01-1.04), environmental (AOR = 1.02,95% CI = 1.004-1.03) and social quality of life (AOR = 1.01,95% CI = 1.006-1.02) were associated with high life skills score. Higher score of neuroticism (AOR = 0.66,95% CI = 0.53-0.79) was associated with low life skills score. CONCLUSION: The results presented provide an opportunity to understand the evolution of factors affecting life skills during the follow-up of this study. This study throws light on development of LSTCP for apparently healthy population in a setting like India and its states.

First-line nivolumab plus ipilimumab in metastatic non-small cell lung cancer: 5-year outcomes in Japanese patients from CheckMate 227 Part 1.

BACKGROUND: In CheckMate 227 Part 1 (NCT02477826), first-line nivolumab plus ipilimumab demonstrated long-term durable overall survival (OS) benefit versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. We report results in Japanese patients with ≥ 5-year follow-up. METHODS: Adults with stage IV/recurrent NSCLC without EGFR/ALK aberrations were randomized 1:1:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy (patients with tumor PD-L1 ≥ 1%), or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (patients with tumor PD-L1 < 1%). Five-year efficacy and safety were assessed in Japanese patients. RESULTS: At 62.1 months' minimum follow-up, 143 Japanese patients with PD-L1 ≥ 1% or < 1% were randomized to nivolumab plus ipilimumab (n = 66) or chemotherapy (n = 77). Five-year OS rates were 46% with nivolumab plus ipilimumab versus 34% with chemotherapy (PD-L1 ≥ 1%) and 36% versus 19% (PD-L1 < 1%). Median duration of response was 59.1 versus 7.1 months (PD-L1 ≥ 1%) and 17.3 versus 3.0 months (PD-L1 < 1%). Among 5-year survivors treated with nivolumab plus ipilimumab (PD-L1 ≥ 1% and < 1%; n = 27), 59% (95% CI, 39%-75%) were off treatment for ≥ 3 years without receiving subsequent therapy. No new safety signals were observed. CONCLUSIONS: At 5-year follow-up, nivolumab plus ipilimumab continued to show long-term durable clinical benefit versus chemotherapy, regardless of tumor PD-L1 expression. Consistent with findings for the global population, these data support the use of nivolumab plus ipilimumab as first-line treatment in Japanese patients with metastatic NSCLC.

Sr doped TiO2 photocatalyst for the removal of Janus Green B dye under visible light.

Hydrothermal synthesis of pristine and Sr doped TiO2 is proposed. The synthesized products were studied for their physiochemical properties. 3% Sr-TiO2 showed a narrow bandgap, which facilitate an increase in oxygen vacancies. The agglomerated morphology was tuned to a nanoball structure after doping with Sr ions. Surface area was increased for the Sr doped TiO2. The samples were used to reduce Janus Green B (JG) dye as a model pollutant. The pure TiO2 showed poor efficiency, while the prepared Sr-TiO2 photocatalyst showed enhanced efficiency with a corresponding increase in the rate constant values of the samples. Tuning of the bandgap, an improvement in the morphology and an increase in the surface area were the major positives of the Sr doped TiO2 samples compared to pure TiO2, 3% Sr-TiO2 is emerging as the best photocatalyst in reducing toxic pollutants. The 3% Sr-TiO2 is a promising candidate for water remediation in the future.

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1.

INTRODUCTION: In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years' minimum follow-up. METHODS: Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only). RESULTS: Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months' minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43-0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66-0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed. CONCLUSIONS: With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.

Gamma irradiation effect on photocatalytic properties of Cu and Sr ions codoped PbS.

Gamma-irradiation effects on photocatalytic action of PbS nanocrystallites codoped with Cu and Sr ions were performed for organic dye degradation. The physical and chemical characterizations of these nanocrystallites were examined employing X-ray diffraction, Raman, and field emission electron microscopic analysis. The optical bandgaps of gamma-irradiated PbS with co-dopants have shifted from 1.95 eV (pristine PbS) to 2.45 eV in the visible spectrum. Under direct sunlight, the photocatalytic action of these compounds against methylene blue (MB) was investigated. Observations indicated that gamma-irradiated Pb(0.98)Cu0.01Sr0.01S nanocrystallite sample exhibits a higher photocatalytic degradation activity of 74.02% in 160 min and stability of 69.4% after three cycles, suggesting that gamma irradiation could potentially influence organic MB degradation. This is due to combined action of high-energy gamma irradiation (at an optimzed dose), which causes sulphur vacancies, and defects created by dopant ions, which alter the crystal structure by inducing strain in the crystal lattice, hence altering the crystallinity of PbS.

Synthesis, properties and antibacterial activity of Ca doped Zn2SnO4 nanoparticles by microwave assisted method.

A major problem in world health care is the development of antibiotic resistance in bacteria. In light of this, pure and calcium-doped zinc tin oxide (ZTO) nanoparticles, Zn2SnO4 (S1), Zn2Sn0.7Ca0.3O4 (S2), Zn2Sn0.5Ca0.5O4 (S3), and Zn2Sn0.3Ca0.7O4 (S4), were synthesized via simple and cost effective microwave assisted method. The doping effect on antibacterial activity was studied in detail. The XRD spectrum revealed that all the deposited samples exhibited a spinel cubic structure. A decrease in crystallite size, an increase in strain and dislocation density was observed with an increase in Ca concentration. FESEM images exhibited an irregular and non-homogeneous nature with crystalline morphology having a physical dimension of nm size. EDAX confirmed the purity of deposited samples. We used the agar well diffusion technique to study the antibacterial activity of Gram-positive and Gram-negative bacteria. The doping of the ZTO matrix with Ca ions increased its antibacterial performance by 99% against Klebsiella pneumoniae bacteria, and its effectiveness was enhanced with increasing Ca ion concentration inside the Zn2SnO4 nanoparticles.

Growth trajectories for executive and social cognitive abilities in an Indian population sample: Impact of demographic and psychosocial determinants.

Cognitive abilities are markers of brain development and psychopathology. Abilities, across executive, and social domains need better characterization over development, including factors that influence developmental change. This study is based on the cVEDA [Consortium on Vulnerability to Externalizing Disorders and Addictions] study, an Indian population based developmental cohort. Verbal working memory, visuo-spatial working memory, response inhibition, set-shifting, and social cognition (faux pas recognition and emotion recognition) were cross-sectionally assessed in > 8000 individuals over the ages 6-23 years. There was adequate representation across sex, urban-rural background, psychosocial risk (psychopathology, childhood adversity and wealth index, i.e. socio-economic status). Quantile regression was used to model developmental change. Age-based trajectories were generated, along with examination of the impact of determinants (sex, childhood adversity, and wealth index). Development in both executive and social cognitive abilities continued into adulthood. Maturation and stabilization occurred in increasing order of complexity, from working memory to inhibitory control to cognitive flexibility. Age related change was more pronounced for low quantiles in response inhibition (ß∼4 versus  -1 versus -0.25 for lower quantiles). Wealth index had the largest influence on developmental change across cognitive abilities. Sex differences were prominent in response inhibition, set-shifting and emotion recognition. Childhood adversity had a negative influence on cognitive development. These findings add to the limited literature on patterns and determinants of cognitive development. They have implications for understanding developmental vulnerabilities in young persons, and the need for providing conducive socio-economic environments.

Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227.

PURPOSE: We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non-small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS: Adults with stage IV/recurrent non-small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS: At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION: With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non-small-cell lung cancer.

The Effectiveness of Virtual Reality in Controlling Pain and Anxiety Levels in Four-to-Six-Year-Old Children During Dental Treatment.

Background and objective Oral health is critical for children's overall well-being; however, dental anxiety often leads to the avoidance of necessary dental care among children. Virtual reality (VR) has emerged as a successful adjunctive tool in various clinical settings, including pain management. This cohort study explores the use of VR technology in reducing anxiety and pain perception during dental procedures for children. The primary objective of this study was to assess the efficacy of VR distraction in managing pain and anxiety levels in children aged four to six years during dental procedures. Additionally, the study aimed to compare children's anxiety levels with and without VR eyeglasses. Methodology This single-blind, crossover clinical trial was conducted at the Dental Complex of King Faisal University, Al Ahsa, Kingdom of Saudi Arabia. Of the 200 children screened initially, 20 aged four to six years who met the inclusion criteria were selected, and ethical approval for the study was obtained. The study comprised two groups: a control group and an experimental group. Dental procedures were conducted both with and without the use of VR, employing a split-mouth design. Results Our findings provide important insights into the clinical impact of using VR technology to alleviate children's anxiety during dental clinic visits. In our study, we used ANOVA and Tukey's post hoc test to evaluate the effect of VR glasses on vital metrics in children during dental procedures. Our results showed no significant differences before and after using the VR glasses, indicating limited effectiveness in reducing anxiety in this context. Conclusion Based on our findings, we reject the assumption that VR devices are highly effective in diverting children's attention and reducing their anxiety and pain during dental procedures; we recommend further investigations to identify potential confounding factors that could modulate the utility of VR in medical settings.

Improving the potential of ethyl acetate green anti-solvent to fabricate efficient and stable perovskite solar cells.

Until now, in all state-of-the-art efficient perovskite solar cells (PSCs), during the fabrication process of the perovskite layer, highly toxic anti-solvents such as toluene, chlorobenzene, and diethyl ether have been used. This is highly concerning and urgently needs to be considered by laboratories and institutes to protect the health of researchers and employees working towards safe PSC fabrication. Green anti-solvents are usually used along with low-performance PSCs. The current study solves the ineptitude of the typical ethyl acetate green anti-solvent by adding a potassium thiocyanate (KSCN) material to it. The KSCN additive causes delay in the perovskite growing process. It guarantees the formation of larger perovskite domains during fabrication. The enlarged perovskite domains reduce the bulk and surface trap density in the perovskite. It enables lower trap-facilitated charge recombination along with efficient charge extraction in PSCs. Overall, the developed method results in a champion performance of 17.12% for PSCs, higher than the 13.78% recorded for control PSCs. The enlarged perovskite domains warrant lower humidity interaction paths with the perovskite composition, indicating higher stability in PSCs.

Simulation and analysis of lead-free perovskite solar cells incorporating cerium oxide as electron transporting layer.

The great demand for renewable energy has greatly contributed to the development of the solar cell industry. Recently, silicon solar cells have dominated the world market. The ease of processing gives perovskite solar cells (PSCs) an advantage over conventional silicon solar cells. Regular silicon photovoltaics require expensive, multi-step processes accomplished in a specialized ultraclean-chamber facility at an elevated temperature (>1000 °C) and highly vacuumed workspace. Hence, researchers and the solar cell industry have focused on PSC as a great rival to silicon solar cells. Despite this, the highest efficiency was obtained from lead-based PSC, which has a considerably high toxicity issue and low stability related to lead content, so the research field pays attention to lead-free perovskite solar cells. In this digital simulation, tin-based perovskite in this paper, methylammonium tin iodide (MASnI3) with the use of cerium oxide (CeO x ) as an electron transporting layer (ETL) with varying percentages of oxygen, which means different shallow donor densities (ND). The optimum value for the thickness of the absorber layer (perovskite) was made, and the current-voltage characteristics and efficiency calculations were also accomplished for the best cell. Then an improvement was made by changing the ND value of CeO x , and the best-optimized cell parameters were: open circuit voltage (V OC) of 0.92 V, short circuit current density (J SC) of 30.79 mA cm-2, power conversion efficiency (PCE) of 17.77%, and fill factor (FF) of 62.86%.

Rare earth metal (Sm)-doped NiMnO3 nanostructures for highly competent alkaline oxygen evolution reaction.

In the present work, samarium-doped nickel manganese oxide was produced by employing a straightforward co-precipitation method. A peak with a 2θ of 36° corresponded to the (110) plane confirming the formation of the rhombohedral crystal structure of NiMnO3. The existence of Mn-O and Ni-O stretching vibration modes was confirmed by Raman spectroscopy. FTIR spectra confirmed the existence of the metal-oxygen bond of NiMnO3. The synthesized ternary Ni-based material was found to be spherical nanoparticles with an average diameter of 0.81 µm. The electrochemical oxygen evolution reaction (OER) performance was explored on 0.02 M samarium (Sm)-doped NiMnO3 demonstrating outstanding OER action with low 321 mV, a low Tafel slope value (109 mV dec-1), and low charge-transfer resistance (0.19 Ω). Moreover, the BET results suggest that the 0.02 M Sm-doped NiMnO3 exhibited elevated surface area (78.78 m2 g-1) with a mesoporous character. Therefore, NiMnO3 doped with high concentrations of a rare earth metal, Sm, is proposed as a suitable material for next-generation water splitting applications.

Conversion and reducing agent effect on zero valent iron into Fe3O4 for photocatalytic degradation under UV light irradiation.

Conversion and reducing agent (NaBH4) effect on zero valent iron into Fe3O4 nanoparticles with diverse molar ratios of reducing agent was produced through chemical reduction technique. The structural, optical, vibrational analyses were executed via XRD, UV-Vis, Raman, and FT-IR analysis. The crystallite size obtained were 35 nm, 27 nm, and 18 nm for Fe:NaBH4 (1:1), Fe:NaBH4 (1:2) and Fe:NaBH4 (1:3). The morphology of the Fe:NaBH4 (1:1) was not in good orientation with higher dimensions. As explored in Fe:NaBH4 (1:2) and (1:3) samples, there is a proper growth of nanoneedles and nanosheets formation. This was due to the addition of reducing agent which greatly helped in enhancement of morphology. The prepared photocatalysts were tested to reduce Malachite Green (MG) under UV illumination. The pure dye solution obtained 57% efficiency after irradiation. Fe:NaBH4 (1:3) photocatalyst achieved 97% efficiency on reducing pollutants. The rate constant values calculated was 0.007, 0.013, 0.02 and 0.03 min-1 for pure, Fe: NaBH4 (1:1), Fe: NaBH4 (1:2) and Fe: NaBH4 (1:3) assisted MG samples. The as prepared photocatalyst is more potential one on removal of toxic pollutants from wastewater which is due to the better enhancement of nanoneedles and nanosheets oriented by the effect of reducing agent. The advantage of Fe3O4 nanoparticles for wastewater is that the removal of these nanoparticles can be ease with magnetic separation methods. On considering the advantage of removing of photocatalyst and efficiency, this prepared product is suitable one for wastewater remediation process in future days.

Investigation of optimum Mn dopant level on TiO2 for dye degradation.

Pristine and Mn-TiO2 photocatalysts was prepared employing sophisticated hydrothermal technique. TiO2, 0.2 M, 0.4 M Mn-TiO2 photocatalysts analysis were done by using standard characterization studies. The morphology of the pure TiO2 photocatalyst showed the large agglomeration of nanoparticles. While the dopant Mn ions influenced higher on host lattice TiO2. The 0.2 M Mn added TiO2 photocatalyst showed no agglomeration and nanoparticles size were decreased. On increasing dopant level, there is growth of nanorods along with nanoparticles which greatly helped in dye degradation. The prepared photocatalysts photocatalytic action was investigated on reducing MG dye. Prepared photocatalyst added dye mixtures were exposed under visible light and collected for every 15 min. 0.4 M Mn-TiO2- MG sample showed 96% efficiency on degrading MG dye. The dopant has increased electrons and holes recombination on host surface. 0.4 M Mn-TiO2-MG sample rate constant was higher than other samples and reaction system abide by Pseudo first order kinetics. 0.4 M Mn-TiO2 photocatalyst be an efficient and enthusiastic potential material to remove organic pollutants.

Effect of grinding time on bismuth oxyhalides optical and morphological properties influence on photocatalytic removal of organic dye.

Herein, we reported the synthesis of BiOX (X = Cl, Br) with different grinding time like 15 min and 30 min to analyze the evolution of physiochemical properties and the morphological evolution. The structural, optical, vibrational properties were examined by standard characterization studies. The formation of bismuth oxyhalides were confirmed by XRD and Raman studies. The crystallite size was decreased as in 30 min grinded sample whereas there is an influence of crystal structure. BiOCl (15 and 30 min) samples expelled the nanoflake like structure with the flakes arranged to form a nanoflower morphology. On comparing BiOCl (15 min), there is high orientation of nanoflakes on BiOCl (30 min) sample. As explored in BiOBr (15 and 30 min) samples, the development of nanoplates were found. The growth of nanoplates was enhanced in the better way in BiOBr (30 min) than BiOBr (15 min). The grinding time has explored a great influence on morphology. The photocatalyst test for prepared photocatalysts was performed to reduce the RhB dye. The photocatalysts showed 74%, 97%, 98% and 99.8% for BiOCl (15 min), BiOCl (30 min), BiOBr (15 min) and BiOBr (30 min). The rate constant value obtained was 0.008, 0.011, 0.021, 0.033 and 0.068 min-1. BiOBr (30 min) sample achieved higher rate constant value. The hierarchical nanostructures and narrow bandgap has made the samples to be a potential candidate to reduce the toxic pollutants with complete efficiency.

Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1,2]-Stevens Rearrangement.

We report enantioselective one-carbon ring expansion of aziridines to make azetidines as a new-to-nature activity of engineered "carbene transferase" enzymes. A laboratory-evolved variant of cytochrome P450BM3, P411-AzetS, not only exerts unparalleled stereocontrol (99:1 er) over a [1,2]-Stevens rearrangement but also overrides the inherent reactivity of aziridinium ylides, cheletropic extrusion of olefins, to perform a [1,2]-Stevens rearrangement. By controlling the fate of the highly reactive aziridinium ylide intermediates, these evolvable biocatalysts promote a transformation which cannot currently be performed using other catalyst classes.