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2023-02-15 15:21:05 By : Ms. Nancy Wong

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Nature Communications volume  13, Article number: 3337 (2022 ) Cite this article

The wide-ranging potencies of bioactive N-fused heterocycles inspire the development of synthetic transformations that simplify preparation of their complex, diverse structural motifs. Heteroaryl ketones are ubiquitous, readily available, and inexpensive molecular scaffolds, and are thus synthetically appealing as precursors in preparing N-fused heterocycles via intramolecular acyl-transfer. To best of our knowledge, acyl-transfer of unstrained heteroaryl ketones remains to be demonstrated. Here, we show an acyl transfer-annulation to convert heteroaryl ketones to N-fused heterocycles. Driven via aromatisation, the acyl of a heteroaryl ketone can be transferred from the carbon to the nitrogen of the corresponding heterocycle. The reaction commences with the spiroannulation of a heteroaryl ketone and an alkyl bromide, with the resulting spirocyclic intermediate undergoing aromatisation-driven intramolecular acyl transfer. The reaction conditions are optimised, with the reaction exhibiting a broad substrate scope in terms of the ketone and alkyl bromide. The utility of this protocol is further demonstrated via application to complex natural products and drug derivatives to yield heavily functionalised N-fused heterocycles.

N-fused heterocyclic compounds, such as pharmaceuticals, agrochemicals, plastics, and dyes (Fig. 1a), are integrated into everyday life1,2,3,4,5,6. Big data analysis shows that heterocycle synthesis is one of the most common reactions in the field of medicinal chemistry7,8. Among the best-selling therapeutics, almost a third contain fused heterocyclic structures9. Due to the high value of N-fused heterocycles, their novel, effective, flexible, general syntheses require investigation10,11,12.

a N-fused heterocycles are ubiquitous within critical molecules, including biologically active natural and synthetic compounds and fine chemicals for use in functional materials. b Transfer-annulation strategy for synthesis of N-fused heterocycles. c Different strategies used in acyl transfer of ketones. d Fused heterocycle synthesis in this study via aromatisation-driven acyl tranfer of heteroaryl ketones with alkyl bromides.

Acyl transfer is a critical process in various biological transformations13. In the field of organic synthesis, acyl transfer is frequently used in formation carbonyl compounds14,15,16,17,18. A typical acyl transfer employs a reactive carboxylic acid derivative (e.g. an acyl chloride or a thioester) as an acyl source. However, whether relatively inert ketones may serve as acyl transfer agents remains unclear?

Ketones are ubiquitous functional groups that not only occur widely in drug molecules and natural products but also act as bulk feedstocks in the syntheses of fine chemicals and materials. They are stable, non-toxic, and simple to prepare via various methods, rendering them ideal synthetic precursors19. If intramolecular acyl transfer of heteroaryl ketones can be realised, a transfer-annulation strategy may be employed in N-fused heterocycle preparation (Fig. 1b). However, owing to the kinetic inertness of C–C bonds, acyl transfer of ketones largely focuses on highly strained ketones20,21,22,23,24,25,26. For unstrained ketones27,28,29,30,31,32, the most common strategy involves using directing groups to form of a stable chelate (Fig. 1c)33,34,35,36,37,38,39,40. Although effective, the use of directing groups complicates the overall synthesis and limits the scope of the accessible products. Hence, a acyl transfer of unstrained ketones for use in N-fused heterocycle synthesis is warranted.

Aromatisation, which enables delocalisation of electron density, stabilising the molecule41, is a critical thermodynamic driving force in the field of organic chemistry42,43,44,45, e.g. aromatisation-driven deacylations of ketones are prominent bond-cleavage strategies46,47,48. Therefore, we conceived a approach for the acyl transfer of unstrained heteroaryl ketones driven by aromatisation of a pre-aromatic intermediate (Fig. 1d). This strategy may be suitable for use in the syntheses of N-fused heterocycles, and, critically, the directing group is no longer required. The next challenge in this strategy is the in situ formation of special, high-energy, pre-aromatic substrates. Transition metal-catalysed dearomatisation is a straightforward strategy to prepare spirocyclic scaffolds49,50,51,52. The spirocyclic intermediates, which are formed in situ from readily available heteroaryl ketones via dearomatisations53,54,55,56, should serve as pre-aromatic precursors to facilitate rearrangement (Fig. 1d). This likely involves a Pd-catalysed dearomative spirocyclisation of a heteroaryl ketone with an alkyl bromide to generate a pre-aromatic intermediate (A), which is then intramolecularly trapped by the heterocyclic nitrogen57,58,59,60,61. The resulting intermediate (B) may subsequently lose a hydrogen, restoring aromaticity to yield the fused heterocyclic product.

Here, we report an acyl transfer-annulation of heteroaryl ketones driven by aromatisation. This method is operationally simple, scalable, and applicable to late-stage modifications of natural products and drug derivatives, which make it a valuable method for the synthesis of organic N-fused heterocycles.

To explore this strategy, we initially used a heteroaryl ketone with a tethered olefin (1), which was prepared in one step using commercially available benzimidazole and 2-vinylbenzoyl chloride, as a model substrate. Because of the unique properties of difluoromethylene group (CF2) and its critical applications in medicinal chemistry62,63,64, ethyl bromodifluoroacetate (BrCF2COOEt) was employed as the coupling partner. After systematic screening, the desired rearrangement product (2) is obtained in a 90% yield using PdCl2 in combination with 1,1-bis(diphenylphosphino)pentane (dpppent, L1) as the ligand and Na2CO3 as the base in dioxane/tetrahydrofuran (THF) (Table 1, entry 1). The structure of 2 was unambiguously determined by X-ray crystallography. In addition, the Pd catalyst appears to be critical in this reaction. Using Pd(OAc)2 or Pd2(dba)3 (dba = dibenzylideneacetone) as the catalyst results in much lower yields (Table 1, entries 2–3), and other metals, such as NiCl2 and FeCl2, are completely ineffective (Table 1, entry 4). A study of the ligand effect further suggests that bidentate phosphine ligands are generally superior, with the yield increasing with the increasing bite angle of the phosphine employed, and L1 is the only ligand that generates full conversion with the optimal yield (Table 1, entry 5). The addition of a base improves the reaction outcome appreciably, likely by neutralising the in situ-generated HBr (Table 1, entry 6). A survey of different solvents reveals that dioxane and THF are individually good, albeit generating slightly lower yields than that obtained using the mixture (Table 1, entries 7–9).

With the conditions determined, the scope of alkyl bromides was examined first (Fig. 2). Ketone 1 is successfully coupled with various alkyl bromides, with 5-, 6-, 7-, or 12-membered cycloalkyls (3–6) generating good yields of the desired coupling products. Heterocyclic bromides, with moieties such as tetrahydropyrane (7) and THF (8), react smoothly, resulting in good yields. Remarkably, the polycyclic bromide derived from the natural steroid stanolone is also amenable to coupling under the reaction conditions (9). Linear alkyl bromides are also suitable for reaction (10–12). We then investigated substrates with a CF2 group. Bromofluoroacetate, bromodifluoromethyl ketone, perfluoroalkyl bromide, bromodifluoromethyl phosphonate, and bromodifluoromethyl sulfone effectively undergo the desired annulation (13–17).

Unless otherwise specified, all the reactions were carried out using ketone 1 (0.1 mmol, 1.0 equiv) and alkyl bromide (0.15 mmol, 1.5 equiv.), PdCl2 (10 mol%), dpppent (12 mol%) and Na2CO3 (1.0 equiv) in dioxane/THF (1:2) at 130 °C. Isolated yields after chromatography are shown.

We further explored the rearrangements of various heteroaryl ketones with bromodifluoroacetate (Fig. 3). The rearrangement took place smoothly by using 2-acylimidazoles and 2-acylbenzimidazoles as substrates (18–41). Both electron-rich and deficient substrates are competent during the cyclization process. A range of functional groups are compatible, including aryl fluorides (28 and 40) and chlorides (20 and 39), trifluoromethyl (21 and 38), esters (23) and cyano (22), are all tolerated. Changing the nitrogen protecting group from methyl to isopropyl (30) and benzyl (31) did not significantly affect the reactivity.

Isolated yields after chromatography are shown. The CCDC number of 43 is 2116753, 52 is 2116752. aThe reaction was performed under optimised condition A: ketone 1 (0.1 mmol, 1.0 equiv) and ethyl bromodifluoroacetate (0.15 mmol, 1.5 equiv), PdCl2 (10 mol%), dpppent (12 mol%) and Na2CO3 (1.0 equiv) in dioxane/THF (1:2) at 120 °C for 24 h. bThe reaction was conducted under optimised condition A with a slight modification: bis(2-diphenylphosphinophenyl)ether (DPEPhos) (12 mol%) was used as ligand during the reaction. cThe reaction was performed under optimised condition B: ketone 1 (0.1 mmol, 1.0 equiv) and ethyl bromodifluoroacetate (0.15 mmol, 1.5 equiv), PdCl2 (10 mol%), dppf (12 mol%) and K2CO3 (1.0 equiv) in dioxane/THF (1:1) at 130 °C for 24 h. dppf = 1,1′-bis(diphenylphosphino)ferrocene.

Compared to the substrate with 4,5-diphenylimidazole (32), the reactions of 4-phenylimidazole (33) and imidazole (34) yield lower conversions, indicating that aromatisation is essential to promote the reaction. Marketed drug-derived ketones, such as ketoconazole (41), also react smoothly despite the presence of several other functional groups. Significantly, numerous substrates are synthesised via direct acylation of commercially available imidazoles or benzimidazoles, with the resulting ketones directly undergoing rearrangement, which further highlights the efficiency of this process. Further, we examined other types of heterocycles, which should yield different heterocyclic cores via rearrangement. Heterocycles such as thiazole (42), benzothiazoles (43–51), benzoxazole (52), and oxazole (53) may also be incorporated, yielding pharmaceutically interesting fused-ring skeletons65,66.

A study was performed to investigate the reaction pathway. To determine whether an alkyl radical exists during this Pd-catalysed process, a radical inhibition study was performed. When 2,2,6,6-tetramethylpiperidinooxy (TEMPO) is added to the reaction mixture, it traps alkyl radicals, indicating that the reaction involves radical species (Fig. 4a). An electron paramagnetic resonance (EPR) study of the reaction of bromocyclopentane with the spin-trapping agent phenyl-N-tert-butylnitrone reveals the presence of spin adducts of the trapped alkyl radicals 56 and 57 (Fig. 4b), as indicated by the EPR spectrum (see supporting information). Deuterium labelling studies were conducted using the heteroaryl ketone D-1 (79% deuterium content) as a substrate under the optimised conditions, with a significant level of the deuterated product D-2 (76% deuterium content) detected, suggesting that there were no reversible hydro-metallation in this process (Fig. 4c)67,68. Finally, we synthesised an aryl Pd complex (58-[Pd]), with 12 produced instead of 59 in the presence of 58-[Pd], benzyl bromide, and 1 (Fig. 4d). Therefore, the alkyl group of the fused heterocyclic product is not derived from the migratory insertion of the Pd(II) complex. The proposed reaction pathway is thus shown in Fig. 4e. The reaction may be initiated by a single electron transfer between Pd(0) and the alkyl bromide, producing hybrid alkyl Pd(I)-radical species INT I. Subsequently, radical addition to the alkene occurs, leading to the hybrid benzylic radical INT II, which then undergoes dearomatisative-spirocyclisation to form the spiro-N-radical INT III. Aromatisation-driven intramolecular acyl transfer may then occur to form the alkyl radical INT IV. Subsequent β-H elimination at the latter yields the product with concomitant regeneration of the Pd catalyst. This proposed mechanism is also supported by X-ray photoelectron spectroscopy, which revealed the presence of three distinct Pd oxidation states (Pd(0), Pd(I), and Pd(II)) during the process, suggesting that Pd(I) species may be involved.

a Radical trapping study using TEMPO showing that alkyl radical species are involved in the reaction. b EPR studies also suggest that this reaction may involve alkyl radicals. c Deuterium labelling studies. d Reaction of 1 with benzyl bromide in the presence of [Ph(PPh3)2PdBr] (58-[Pd]). e A proposed reaction pathway.

Further studies were conducted to demonstrate the viability of this acyl transfer-annulation strategy. The protocol was applied in the late-stage modifications of natural products and drug derivatives (Fig. 5a). Various complex molecules with diverse structural features, such as steroids (62 and 69), N-heteroarenes (oxazole 63 and indole 68), alkaloids (66), and carbohydrates (72), are readily converted into the corresponding products in useful yields. This strategy provides a straightforward, versatile method of generating valuable N-fused heterocyclic moieties within complex molecules. Given the ubiquity of N-fused heterocycles in pharmaceuticals, this approach may be used in the field of medicinal chemistry.

a Using the tranfer-annulation strategy in the late-stage modifications of complex frameworks based on natural products and drug molecules. b Gram-scale synthesis and various useful transformations of 2. The CCDC number of 74 is 2131840.

To showcase the scalability of this process, a gram-scale reaction was carried out. Gratifyingly, a satisfactory 67% isolated yield (80% yield based on recovered 1) of product 2 could be obtained without modification of the optimised conditions (Fig. 5b). The N-fused heterocyclic scaffold can readily undergo various transformations to access a range of synthetically useful scaffolds. For example, the bromination of 2 proceeded to afford 74, excellent selectivity for the 9-position was observed, which allows follow-up fused heterocycle manipulations through cross-couplings. Treatment with mCPBA, deconstruction of N-fused heterocycle was observed, which afforded 75 in 53% yield. Diazidation product 76 was afforded in 48% yield via vicinal diazidation of olefin. Moreover, the ester moiety was smoothly reduced with NaBH4, affording the corresponding alcohol 77 in 68% yield.

In conclusion, a synthetically useful, mechanistically intriguing intramolecular acyl transfer of heteroaryl ketones was developed, which was suitable for use in fused-ring synthesis. The formation of a high-energy pre-aromatic spirocyclic intermediate was critical in the successful transformation, with aromatisation the driving force that facilitated C–C bond cleavage. Given the ready availability of the ketone moiety, this strategy could be used to simplify the syntheses of complex N-fused heterocyclic systems, which are privileged structures within numerous biologically active compounds. Moreover, the protocol enabled the late-stage modifications of intricate natural products and drug derivatives and may thus facilitate heterocyclic drug discovery.

In a nitrogen-filled glovebox, an oven-dried 10 mL sealed tube equipped with a Teflon-coated magnetic stir bar was charged successively with heteroaryl ketone 1 (0.1 mmol), alkyl bromide (0.15 mmol, 1.5 equiv), PdCl2 (0.01 mmol, 10 mol%), dpppent (0.012 mmol, 12 mol%), Na2CO3 (0.1 mmol, 1.0 equiv) and dioxane/THF (1.0 mL, 1:2). The tube then was sealed with a Teflon screw cap, moved out of the glovebox, and placed on a hotplate pre-heated to 130 °C for 24–36 h. After completion of the reaction, the mixture was filtered through a thin pad of silica gel. The filter cake was washed with ethyl acetate and the combined filtrate was concentrated under vacuum. The residue was purified via silica gel chromatography.

In a nitrogen-filled glovebox, an oven-dried 10 mL sealed tube equipped with a Teflon-coated magnetic stir bar was charged successively with heteroaryl ketone 1 (0.1 mmol), difluorobromoethyl ester (0.15 mmol, 1.5 equiv), PdCl2 (0.01 mmol, 10 mol%), dppf (0.012 mmol, 12 mol%), K2CO3 (0.1 mmol, 1.0 equiv) and dioxane/THF (1.0 mL, 1:1). The tube then was sealed with a Teflon screw cap, moved out of the glovebox, and placed on a hotplate pre-heated to 120 °C for 24 h. After completion of the reaction, the mixture was filtered through a thin pad of silica gel. The filter cake was washed with ethyl acetate and the combined filtrate was concentrated under vacuum. The residue was purified via silica gel chromatography.

Data relating to the optimisation studies, mechanistic studies, general methods, and the characterisation data of materials and products, are available in the Supplementary Information. Crystallographic parameters for compounds 2, 43, 52 and 74 are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 2116750 (2), 2116753 (43), 2116752 (52) and 2131840 (74). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

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We are grateful for the financial support from the National Natural Science Foundation of China (21971205), Key Research and Invention Program in Shaanxi Province of China (2021SF-299), Natural Science Basic Research Program of Shaanxi (2020JQ-574), Scientific Research Program of Shaanxi Education Department (No. 20JK0937) and Northwest University.

These authors contributed equally: Dan Ye, Hong Lu.

Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, 710069, Xi’an, China

Dan Ye, Hong Lu, Yi He, Jinghao Wu & Hao Wei

College of Food Science and Technology, Northwest University, 710069, Xi’an, China

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H.W. conceived and designed the project and composed the paper. D.Y., H.L., Y.H. and J.W. conducted the experiments and analysed the data. H.L. and Z.Z. discussed the experimental results and commented on the paper. H.W. conducted general guidance, project directing, and paper revisions.

The authors declare no competing interests.

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Ye, D., Lu, H., He, Y. et al. Rapid syntheses of N-fused heterocycles via acyl-transfer in heteroaryl ketones. Nat Commun 13, 3337 (2022). https://doi.org/10.1038/s41467-022-31063-3

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oxidative stress and pro-inflammatory condition at schizophrenia77.

Due to the synthesis of T4 and functioning of GPX3 are determined by selenium, we cannot bypass the potential role of SELENOP, which interconnects GPX3 activity with thyroid hormones releasing78 (Fig. 3, Table 1). Its responsibilities are focused on the transfer of selenium in the tissues, including the brain, and antioxidant functions. The observed elevation (Supplementary Appendix C) can be caused by a higher demand of selenium due to both upregulated GPX3 and T4 biosynthesis on the background of subclinical hypothyroidism.

There have been far few studied about the positive association between thyroid-stimulating hormone (TSH) and prolactin but symptoms of hyperprolactinemia on the background of hypothyroidism are usually observed79. In this study, we found cautioning reduction of L-3,5-diiodotyrosine and thyroxine hormones (Table 2) interconnected with dopamine and catecholamines uptake (hsa00350 and hsa04918 pathways; Fig. 4). But only GPX3 with inclusion of two SNPs (rs8046 and rs10306166) is co-associated with the regulation of thyroid hormones synthesis and considered as an entering point of arachidonic acid metabolism and serotonergic synapse transmission (Table 3). Other studies indicated a relationship between the severity of schizophrenia and the diminished synthesis of T3 andT4, and T4 is lowering more apparent. However, there was no difference in TSH compared to the control group80.

The tacit assumption is that subclinical hypothyroidism is regular for schizophrenia patients, but some research witnesses about its association with antipsychotic medication81. There is no unambiguous opinion, but T4 increases gradually at schizophrenia, although data were related to the first hospitalization and attributed to stressful situation as a consequence of neuroprotective modulation81. Generally, there is a gentle tendency to the decrease of T4, which positively affects the prolactin level in patients with schizophrenia80,81. In turn, prolactin sends a positive effect on APOD and inhibits adiponectin, thus reducing the concentration of aromatic steroids. Due to estradiol inversely correlates with oxidative stress (through FASN and APOD; Fig. 3), it greatly contributes to the increased risk of oxidative stress.

Insofar our concept fits into the deployed proteomic-metabolic framework (Figs. 3, 4), we encouraged further investigation of association between serotonin, tyrosine, T4 and dopamine. It is known that the elevated dopamine entails to the decrease of TSH and T4. This is supported by the data for therapy by the dopamine receptor blockers leading to subclinical hypothyroidism and hyperprolactinemia that causes the elevation of TRH.

There are clinical observations establish a strong negative correlation between 5-hydroxyindolylacetic acid (5-HIAA) with T3 and TSH in patients with schizophrenia. It is essential to understand that T4 and TSH impacts nor serotonin secretion per se but the population (density) of serotonin receptors and, therefore, their vulnerability to serotonin82,83. Substitutional therapy of schizophrenia with TSH and treatment of depression with T4 reliably improves amelioration of patients and delivers a positive effect on the level of serotonin due to the increased perceptivity of 5-HT receptors84. Otherwise, the increase of 5-HIAA is recognized due to a stoichiometric shift between serotonin and its receptors towards the ligand of the receptor.

Normetanephrine as a catecholamine (Supplementary Appendix D), is a deactivated product of norepinephrine, and a product of tyrosine transformation. There are extensive data on the substantial role of catecholamines in the severity of schizophrenia85,86. The axis of norepinephrine and serotonin via diencephalon into the limbic system and the cerebral cortex plays a considerable role emotional component of human’s life. Patients with the compromised noradrenergic transmission are characterized by the increased T3 in brain nuclei since norepinephrine is a T3 co-transmitter in noradrenergic signal transduction87.

Thus, depletion of catecholamines typically accompanies a deficiency of serotonin. Indeed, the level of norepinephrine and normetanephrine is lower in patients with schizophrenia (Supplementary Appendix D). There is considerable evidence that the decrease is caused by the reduced activity of brain monoamine oxidase (MAO-B) in patients with schizophrenia88, which is complementary with our data. In this respect, the role of estrogen in schizophrenia pathogenesis is severely important, since estrogen positively regulates dopamine activity. Thus the deficiency in estrogen obviously entails to the increased catechol-O-methyltransferase activity and, consequently, to the decreased dopaminergic transmission. That is the reason of why, medication in combination with estrogens restores dopamine receptors sensibilization and provides amelioration of psychotic symptoms89.

We admit, that medications used for schizophrenia treatment may occasionally produce a significant impact on the reconstructed image of the molecular event in the proposed connective model. Still, the complete view is doubtful due to the high complexity of schizophrenia pathology; however, the interplay between the functions of lipids transport/metabolism, thyroid hormone synthesis, and steroidogenesis more than merely evident (Fig. 4).

Up to nowadays, diagnostics of schizophrenia is burden of responsibility of the expertized physician. The lack of clinically relevant serological or metabolic markers is fraught with difficulties in differentiation of schizophrenia from bipolar disorder or depression syndrome. In this study, we tried to combine three interplaying layers (genome, proteome, and metabolome) to overview molecular events at schizophrenia. Although the majority of data were extracted from the metabolic and proteomic assay, because the GWAS data are beyond the scope of the confidence, yet they sufficiently play a symphony of events, which are involved in the etiology and pathogenesis of schizophrenia. The proposed graph (Fig. 4) consolidates extracted biological pathways that cover defined metabolites and proteins, and integrates elements omitted in the study but previously associated with schizophrenia. Data collected in the study reflect a multifaced chain of proportional events that instruct the immune response, compromised lipids transport, and signs of lysosomal accumulation. The largest centralities (Fig. 4) integrate proteome re-arrangements that are accompanied by manifested impairment os steroidogenesis and hypothyroidism, which are tightly linked with cAMP-mediated signaling and tyrosine metabolism. These processes affect the perceptivity of 5-HT receptors and thyroid-supplemented noradrenergic transmission.

It seems that not so much lipids metabolism (including PPAR signaling) but lipids transport contributes in disturbance of biological processes in schizophrenic patients, which supports the relation of schizophrenia to neurodegenerative disease. On the other hand, imbalance in steroidogenesis (Table 2) and related proteins (Table 1) favors over imbalance in thyroid-related and catecholamines endocrine axis. It is hard to overestimate the role of steroids, thyroid hormones, and catecholamines, because all of them are covered by neuroactive ligand-receptor interaction (one of five largest centrality; Fig. 4) and at the same they spread among a few more specialized centralities including estrogen signaling, axon guidance, glutamatergic and dopaminergic synapse plasticity (Fig. 4).

A series of independent investigations elsewhere on significantly larger cohort of patients with schizophrenia is essential and can provide a vanquish above the obvious limitations of this study. No words exaggerating the performance of such collaboration to consolidate proteomic, metabolomic, and genotyping for rigorous reconstruction of probably one of the most enigmatic diseases. It is even much more feasible if render a convolutional neural network for proteomic and metabolomic data that recently has been successfully realized for the classification and determination of schizophrenia comorbidity90 as a tool complementary to the conventional systematic approach.

Apart from the small size of study population even together with the validating cohort, the background derived from multidrug therapy is by far one of the main challenging tasks in research of schizophrenia. Treatment strategy may cause a great influence on the final result and may require correction actions to align between patient’s assessment and metabolic background that shadowed by medications. In this study we draw the attention on the huge number of drug and drug-like metabolites observed in serum samples which were excluded from the consideration and required additional statistical actions to avoid biases.

Urea (99%) and formic acid (98%+, pure) were obtained from Acros Organics (Geel, Belgium). Trifluoroacetic acid (99%, Reagent Plus®), triethylammonium bicarbonate (1 M solution), 4-vinylpyridine (95%), sodium deoxycholic acid (> 97% titration) were from Sigma (St. Louis, MO, USA). Acetonitrile (HPLC grade, filtered for 0.2 µm) was purchased from Fisher Chemical (Loughborough, UK). Acetic acid (EMSURE®, glacial, anhydrous for analysis) was from Merck (Darmstadt, Germany). TCEP (Tris(2-carboxyethyl) phosphine hydrochloride) was purchased from Pierce™ (Thermo Fisher, Rockford, IL, USA). Trypsin (sequencing grade modified), 5 vials × 20 µg, lyophilized powder (Promega; Madison, WI, USA). β‐glucuronidase from Escherichia coli K12 strain, 5 ml falcon vial, specific activity ~ 140 U/mg at 37 °C (Roche Diagnostics GmbH; Germany). Water (TOC < 3 ppb) was obtained from Milli-Q Integral 3 purification system, Millipore S.A.S (France). Oasis® 3 cc (cubic centimeter) nominal volume, 60 mg resin, type of resin: WAX—weak anion exchange (Waters Corporation; Milford, MA, USA). d5-betamethasone, 1 mg, powder (catalogue number: B327002; Toronto Research Chemicals; Toronto, ON, Canada). UPS-2—Universal Proteomics Dynamic Range Standard, 10.6 µg, dynamic range: 0.5 fmoles—50,000 fmoles; 48 different proteins (Sigma; Saint Louis, MO, USA).

The study design was approved by the local Ethical Committee of the Alexeev N.A. 1st Clinics of Mental Health, (Moscow; AXM-EH2019-R017.G12 issued on February 15, 2019; AXM-EH2020-R004.Y04 issued on March 4, 2020). All handlings and use of material were provided according to the WMA Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects (revision Fortaleza, 2013). All the participants were aware of the research purpose. Informed consent was obtained from all participants of the control group and informed consent was obtained from a parent and/or legal guardian of participants of the assay group.

We enrolled totally n = 127 subjects for this study among which n = 49 subjects were being schizophrenic subjects who were accepted for inpatient, n = 50 were healthy volunteers aligned by anthropometric data (age, genders ration, BMI). Additionally, n = 28 schizophrenic subjects and n = 11 healthy volunteers (n = 39 subjects in total) were recruited for rendering of the validation study (Table 4). Subjects matched for age and gender ratio and were examined in terms of severity of catatonic, positive and general symptoms, and degree of cognitive impairments. Most of the observed patients with schizophrenia (~ 60%) burden a prevalence of hereditary loading. Details of clinical and psychometric characteristics are in Supplementary Appendix A.

We selected patients in both study and validating cohorts (Table 1) aligned in the majority of sociodemographic and psychometric parameters. These two groups matched in age at onset of prodromal symptom, at manifested syndrome, at onset of first psychotic symptoms and at first hospitalization where statistical significance exceeded p > 0.83 meaning the lack of differences between patients. The same matches were reached in regard of psychometric characteristics based on the main scales and scores routinely used in clinical psychiatry (PANSS, BFCR, NCS4 and DSM-5). The attained alignment legalized employment of the validating group to control and correct, if necessary, the hypothesized molecular mechanisms originally extracted from the proteome, metabolome and genome-wide associated studies of the assayed group of patients with schizophrenia disputed it was combined from those who had no previous testimony of the disease history and those who had been qualified as resistant to medication and therapy for a long time (more than 10 years) from the manifestation.

The control group consisted of healthy volunteers, matched by age and gender, who had no history of mental disorders and were not on any medications; none of the respondents had a history of serious physical illness, including cardiac, cancer or neurological disorders.

Proteomic analysis of plasma samples was performed as described in Ref.91. Briefly, we used 100 µg of protein fraction (about 2 µL) for proceeding and digestion with trypsin. Details of proteomic samples preparation are available in Supplementary Appendix-B (section no. 2). Metabolomic analysis was accomplished as described in Ref.92 with minor modifications. Briefly, 100 µL of plasma was fortified with d5-betamethasone (ISTD) and supplied with SPE/LLE extraction. Details of metabolomic sample preparation are available in Supplementary Appendix B (section no. 4).

Proteomic analysis was performed on an ultra-high-resolution Orbitrap Fusion mass spectrometer equipped with a nanoflow Ultimate 3000 UPLC (both from Thermo Fisher, Germany) as described in Ref.91. A survey of metabolomic compounds was conducted on a high-resolution G6550 Q-TOF mass spectrometer with a 1290 Infinity UPLC (both from Agilent, Germany). Details are given in Supplementary Appendix B (sections no. 3 and no. 7 for proteomic analysis, and sections no. 5 and no. 8 for metabolomic analysis). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE93 partner repository with the dataset identifier PXD035863 and https://doi.org/10.6019/PXD035863.

Case (48 patients with schizophrenia) and control “1000 Genomes Phase 3” (200 volunteers) are taken from the same European population. Total DNA was isolated using QIAamp DNA (Qiagen, Germany). Case (48 patients with schizophrenia) and control “1000 Genomes Phase 3” (200 volunteers) are taken from the same European population. Sample handled on an Illumina HiScan (San Diego, CA, USA) and genotyped for 652,297 markers for 231 subjects, of which 48 cases and 183 controls, on an Infinium Global Chips Screening Array-24v2.0 using the IMPUTE2 program with parameters Ne = 20,000 and k = 90. Additional filtering was performed by metrics INFO > 0.5 and genotype probability > 0.5. Quality Control allowing only 2% of missing SNPs was performed separately in each individual dataset and Association Search was conducted using the plink version 1.90b6.7 program. The GWAS of patients with schizophrenia was performed using logistic regression with imputation probabilities adjusted for PCA covariates, chosen as nominally significant with p < 0.05 in the employed logistic regression. Control of the homogeneity of the obtained samples was carried out using a PCA made by smart-PCA version13050 EIGENSOFT version 7.2.0 package94 (Supplementary Appendix E). To avoid overloading the GWAS by adding too many covariates to the regression model, only the first 10 principal components were considered and tested for inclusion. The final set of covariates included the first five principal components as recommended for most GWAS approaches. Details of the analysis and results are given in Supplementary Appendix B (section no. 9) and Appendix E.

Quantitative analysis for proteomics was performed as described in Ref.95. The UPS-2 (Sigma; Saint Louis, MO, USA) employed to plot the calibration curve and fit the meaningful proteins. Details of quantitation are acknowledged in Supplementary Appendix B (section no. 6).

Statistical analysis was performed on an R-package, and complete details are available in Supplementary Appendix B (section no. 10). The significance of anthropometric and psychometric items between the studied groups was performed by a two-sided t-test at a p-value cut-off p < 0.05. Due to the small size of the studied groups, significance in the measured concentrations of proteins and metabolites was evaluated by Wilcoxon’s test with significance level cut-off p < 0.05. To achieve data reduction and discrimination, principal component analysis (PCA) and pairwise Student’s t-test at p < 0.05 were applied to the total proteome and metabolome identified in both control and assayed (subjects with schizophrenia) groups. To perform variable selection and classification of the studied cohort, sparce partial least-squares discriminant analysis (sPLS-DA) with 0.95 ellipse area confidence level was utilized. To be selected from the total proteome, the candidate protein shall meet the criterion of unicity when more than one (ni(p) > 1) unique peptide shall be met for the certain protein among the totality of peptides Acceptance criteria for the protein identification were based on the Human Proteome Project Mass Spectrometry Data Interpretation Guidelines 3.096. NSAFs (Normalized Spectra Abundance Factor) were summarized for each protein within the studied groups, and data with zero means were imputed. A measure of protein abundance was represented as a median value fold changes (FC) ratio toward the control group and calculated based on the absolute concentration sampled from the UPS-2 (see Supplementary Appendix B for details). For metabolites, the criteria of frequency exceeding one occasion within each studied group were significant. The significance scores obtained after identification of metabolite compounds (Supplementary Appendix B section no. 8 for more details) were averaged within each studied group, and zero means were imputed. Proteins and metabolites with a frequency exceeding 0.85 and the fold changes cut-off > 2 or < 0.5 at a p-value less than 0.05 were considered as significant in quantitative property. To revealed outliers and significant differences in a quantitative loading we applied Wilcox test with Benjamini–Hochberg correction for multiple hypothesis testing, and the adjusted p-values were plotted on Volcano against the calculated fold changes. Proteins and metabolites, significantly altered between the studied groups, were extracted and submitted for functional and pathways annotation analysis at a q-value threshold less than 0.01 using Gene Ontology (GO) toolset against the complete human genome as a reference list. The enriched terms were refined with a similarity coefficient of > 0.7 to remove the redundant terms. The refined terms were associated with the protein and metabolite lists drawn up for the studied groups and adjusted with KEGG means and Reactome pathway terms to consolidate observed proteins, metabolites and associated loci with the current knowledge into centrality graph. All other analyses were performed with the in-house scripts written in R (version 3.2.0; R Foundation for Statistical Computing, Vienna, Austria; https://www.r-project.org/).

The datasets generated and/or analyzed during the current study are available in the PRIDE93 (Proteome Exchange) repository under registered ID: PXD035863 (or following link: https://doi.org/10.6019/PXD035863).

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This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers ‘Digital Biodesign and Personalized Healthcare’ (ref. no 75-15-2022-305).

These authors contributed equally: Arthur T. Kopylov, Alexander A. Stepanov, Kristina A. Malsagova, Natalia V. Zakharova, Georgy P. Kostyuk and Anna L. Kaysheva.

Biobank Group, Department of Proteomic Research, Institute of Biomedical Chemistry, 10 Pogodinskaya Str., Bld. 8, Moscow, Russian Federation, 119121

Arthur T. Kopylov, Alexander A. Stepanov, Tatiana V. Butkova, Kristina A. Malsagova, Artem U. Elmuratov & Anna L. Kaysheva

Alexeev N.A. 1St Clinics for Mental Health, 2 Zagorodnoe Road, Moscow, Russian Federation, 115119

Natalia V. Zakharova & Georgy P. Kostyuk

Center for Medical Genetics “Genotek”, 17/1 Nastavnichesky Lane, Moscow, Russian Federation, 105120

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A.T.K. and A.L.K. provided study design and conceptualization; A.A.S. made statistical analysis; K.A.M. conducted samples preparation and primary data analysis and interpretation; A.T.K. made methods development and validation assay; T.V.B. is responsible for source and clinical data curation; N.V.Z. and G.P.K. performed curation of clinical data and selection of patients; A.U.E. designed and performed G.W.A.S. analysis and primary data processing; A.T.K. and A.L.K. performed reconstruction of the connective model.

Correspondence to Arthur T. Kopylov.

The authors declare no competing interests.

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Kopylov, A.T., Stepanov, A.A., Butkova, T.V. et al. Consolidation of metabolomic, proteomic, and GWAS data in connective model of schizophrenia. Sci Rep 13, 2139 (2023). https://doi.org/10.1038/s41598-023-29117-7

DOI: https://doi.org/10.1038/s41598-023-29117-7

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