Amino Derivatives Research Articles

Electron tunneling through interim ligand layers towards photoredox selective organic transformation

Photocatalytic selective organic transformation represents an emerging avenue for artificial photosynthesis toward renewable solar energy conversion. However, solar-to-chemical conversion efficiency in photocatalysis is largely hampered by the sluggish charge transfer kinetic and difficulty in precise control over the charge migration pathway. Herein, we demonstrate conceptually new metal–insulator–semiconductor (MIS) electron tunneling photosystems to finely modulate the directional charge flow for photoredox selective organic transformation. The ultrathin insulating organic ligands layers capped on the surfaces of metal nanocrystals (NYs) and transition metal chalcogenides quantum dots (TMCs QDs) mutually function as precise directing-mediums to stimulate spontaneous electrostatic self-assembly between the tailor-made oppositely charged metal NYs and TMCs QDs for constructing metal (Au, Pd) NYs/TMCs (CdSe, CdS) QDs heterostructured electron tunneling photosystems. The electrons photoexcited from TMCs QDs can be efficaciously extracted and tunneled to metal NYs across the intermediate insulating hierarchical ligands layers to participate in the photoredox catalysis. The metal NYs-insulating ligands-TMCs QDs photosystems can efficiently mediate the minority carrier transport across the intermediate insulating ligand layers with minimal recombination, thereby resulting in the significantly enhanced net efficiency of multifarious photoactivities toward selective organic transformation including anaerobic photoreduction of nitroaromatics to amino derivatives and selective photo-oxidation of aromatic alcohols to aldehydes under visible light irradiation. The ligand-triggered electron tunneling effect has been evidence to be universal. Our work would inspire ongoing interest in exploring diverse organic ligands-based charge tunneling photosystems and provide a valuable roadmap for substantial solar energy conversion.

Enantioselective Catalyzed Synthesis of Amino Derivatives Using Electrophilic Open‐Chain N‐Activated Ketimines

AbstractN‐Activated ketimines are characterized by the presence of acyl, sulfonyl, and phosphinoyl groups linked to the nitrogen atom of the azomethine system. These electron‐withdrawing groups enhance the electrophilic character of the imino moiety allowing the addition of even weak nucleophilic reagents. The presence of the oxygen atoms in these activating groups with its coordinating and Lewis or Brønsted properties is of paramount importance in asymmetric catalyzed reactions. This review collects the results that have appeared in the literature during the last two decades on the utilization of open‐chain N‐activated ketimines for the synthesis of optically active α‐disubstituted and α‐trisubstituted amino derivatives including nitrogen‐containing heterocyclic compounds.magnified image

Intercalating ultrathin polymer interim layer for charge transfer cascade towards solar-powered selective organic transformation

Transition metal chalcogenide quantum dots (TMCs QDs) constitute a crucial sector of semiconductors on account of large absorption coefficient for light harvesting, peculiar quantum confinement effect, and abundant active sites stemming from ultra-small size. However, elaborate and tunable modulation of anisotropic photoinduced charge carriers over TMCs QDs represents an enduring challenge in terms of sluggish charge transfer kinetic and ultra-short charge lifetime compared with nanoparticulate counterparts, thereby rendering maneuvering charge transfer of TMCs QDs a tough issue. We herein conceptually unlock the unanticipated charge transport capability of solid-state non-conductive poly(diallyl dimethylammonium chloride) (PDDA) for constructing cascade charge transfer pathway over self-assembled wide bandgap semiconductors (WBS)/PDDA/TMCs QDs multilayered heterostructures, by which unidirectional and accelerated electron transfer from TMCs QDs to WBS support mediums was spontaneously activated, markedly boosting the charge separation/migration efficiency. The integrated roles of such ultrathin insulating PDDA intermediate layer as simultaneous surface charge modifying agent and interfacial charge transfer mediator have been evidenced to be universal. The unexpected electron-withdrawing capability of ultrathin PDDA layer endows WBS (SnO2, TiO2)@PDDA@TMCs (CdSe, CdS) QDs heterostructures with significantly enhanced net efficiency of photoactivities toward selective anaerobic reduction of nitroaromatics to amino derivatives under visible light irradiation. Our work would feature a promising scope for rational design of multifarious novel insulating polymers-based photosystems for solar energy conversion.

A Comprehensive Targeted Metabolomics Assay for Crop Plant Sample Analysis.

Metabolomics plays an important role in various fields from health to agriculture. However, the comprehensive quantitative metabolomic analysis of plants and plant metabolites has not been widely performed. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based plant metabolomics offers the sensitivity and breadth of coverage for both phenotyping and disease diagnosis of plants. Here, we report a high-coverage and quantitative MS-based assay for plant metabolite analysis. The assay detects and quantifies 206 primary and secondary plant metabolites, including many key plant hormones. In total, it measures 28 amino acids and derivatives, 27 organic acids, 20 biogenic amines and derivatives, 40 acylcarnitines, 90 phospholipids and C-6 sugars. All the analysis methods in this assay are based on LC-MS/MS techniques using both positive and negative-mode multiple reaction monitoring (MRM). The recovery rates of spiked plant samples at three different concentration levels (low, medium and high) ranged from 80% to 120%, with satisfactory precision values of less than 20%. This targeted plant metabolomic assay has been successfully applied to the analysis of large numbers of pine and spruce needle samples, canola root samples, as well as cannabis samples. Moreover, the assay was specifically developed in a 96-well plate format, which enables automated, high-throughput sample analysis. This assay has already been used to analyze over 1500 crop plant samples in less than two months.

Synthesis and Molecular Docking of Some Grossgemin Amino Derivatives as Tubulin Inhibitors Targeting Colchicine Binding Site

Six amino derivatives of grossgemin (2–7) were synthesized according to the reported essential pharmacophoric features of colchicine binding site inhibitors (CBSIs). The derivatives 4–6 were obtained for the first time. The pharmacophoric features of 2–7 as CBSIs were studied to be almost identical. Furthermore, the 3D-flexible alignment of compound 5 as a representative example with colchicine showed a very good overlapping. In agreement, compounds 2–7 docked into CBS with binding modes very similar to that of colchicine and exhibited binding free energies of −24.57, −25.05, −32.16, −29.34, −26.38, and −26.86 (kcal/mol), respectively. The binding free energies of 4–7 were better than that of colchicine (−26.13 kcal/mol) with a noticeable superiority to compound 4.

High-Throughput LC-ESI-MS/MS Metabolomics Approach Reveals Regulation of Metabolites Related to Diverse Functions in Mature Fruit of Grafted Watermelon.

Grafting has been reported as a factor regulating the metabolome of a plant. Therefore, a comprehensive metabolic profile and comparative analysis of metabolites were conducted from fully mature fruit of pumpkin-grafted watermelon (PGW) and a self-rooted watermelon (SRW). Widely targeted LC-ESI-MS/MS metabolomics approach facilitated the simultaneous identification and quantification of 339 metabolites across PGW and SRW. Regardless of grafting, delta-aminolevulinic acid hydrochloride, sucrose, mannose-6-phosphate (carbohydrates), homocystine, 2-phenylglycine, s-adenosyl-L-homocysteine (amino acids and derivatives), malic, azelaic, H-butanoic acid ethyl ester-hexoside isomer 1, (organic acids), MAG (18:3) isomer1, LysoPC 16:0, LysoPC 18:2 2n isomer (lipids) p-coumaric acid, piperidine, and salicylic acid-o-glycoside (secondary metabolites) were among the dominant metabolite. Dulcitol, mono-, and disaccharide sugars were higher in PGW, while polysaccharides showed complex behavior. In PGW, most aromatic and nitrogen-rich amino acids accumulated greater than 1.5- and 1-fold, respectively. Intermediates of the tricarboxylic acid cycle (TCA), stress-related metabolites, vitamin B5, and several flavonoids were significantly more abundant in PGW. Most lipids were also significantly higher in grafted watermelon. This is the first report providing a comprehensive picture of watermelon metabolic profile and changes induced by grafting. Hence, the untargeted high-throughput LC-ESI-MS/MS metabolomics approach could be suitable to provide significant differences in metabolite contents between grafted and ungrafted plants.

Synthesis of New Amino-β-Cyclodextrin Polymer, Cross-Linked with Pyromellitic Dianhydride and Their Use for the Synthesis of Polymeric Cyclodextrin Based Nanoparticles.

New water soluble amino β-cyclodextrin-based polymer was synthesized by reaction between amino cyclodextrin derivatives and pyromellitic anhydride. This experiment presents amino derivatives, which were synthesized by attaching amino groups to β-cyclodextrins (β-CDs) used mono-6-azido-6-deoxy-β-cyclodextrin (β-CD-N3) and triphenylphosphine (Ph3P) in anhydrous N,N-dimethylformamide (DMF). An amino blocking reaction was conducted. The obtained polymer was purified by ultrafiltration. In addition, an attempt was made to create nanospheres by encapsulating the polymer with chitosan (CT) in an acidic condition. For the first time, nanospheres were obtained in the reaction between an amino β-cyclodextrin polymer and chitosan. Scanning electron microscopy (SEM). 1H NMR and ESI-MS methods for confirmation of reaction product and for structural characterization were employed. The differential scanning calorimetry (DSC) studies of polymers were also carried out.

Halobellus ruber sp. nov., a deep red-pigmented extremely halophilic archaeon isolated from a Korean solar saltern.

A novel halophilic archaeon, strain MBLA0160T, was isolated from a solar saltern in Sorae, Republic of Korea. The cells are deep-red pigmented, Gram-negative, rod shaped, motile, and lysed in distilled water. The strain MBLA0160T grew at 25-45°C (optimum 37°C), in 15-30% (w/v) NaCl (optimum 20%) and 0.1-1.0M MgCl2 (optimum 0.3-0.5M) at pH 5.0-9.0 (optimum 7.0). Phylogenetic analysis based on the 16S rRNA sequence showed that this strain was related to two species within the genus Halobellus (Hbs.), with 98.4% and 95.8% similarity to Hbs. salinus CSW2.24.4T and Hbs. clavatus TNN18T, respectively. The major polar lipids of the strain MBLA160T were phosphatidylglycerol, phosphatidylglycerol sulfate, and phosphatidylglycerol phosphate methyl ester. The genome size, G + C content, and N50 value of MBLA0160T were 3.49Mb, 66.5mol%, and 620,127bp, respectively. According to predicted functional proteins of strain MBLA0160T, the highest category was amino acid transport and metabolism. Genome rapid annotation showed that amino acid and derivatives was the most subsystem feature counts. Pan-genomic analysis showed that strain MBLA0160T had 97 annotated unique KEGG, which were mainly included metabolism and environmental information processing. Ortholog average nucleotide identities (OrthoANI) and in silico DNA-DNA hybridization (isDDH) values between the strain MBLA0160T and other strains of the genus Halobellus were under 84,4% and 28.1%, respectively. The genome of strain MBLA0160T also contain the biosynthetic gene cluster for C50 carotenoid as secondary metabolite. Based on the phylogenetic, phenotypic, chemotaxonomic properties, and comparative genomic analyses, strain MBLA0160T is considered to represent a novel species of the genus Halobellus, for which the name Halobellus ruber sp. nov. is proposed. The type strain is MBLA0160T (= KCTC 4291T = JCM 34172T).

Molecular docking studies, in-silico ADMET predictions and synthesis of novel PEGA-nucleosides as antimicrobial agents targeting class B1 metallo-β-lactamases.

Class B1 metallo-β-lactamases (MBLs) are metalloenzymes found in drug resistant bacteria. The enzyme requires zinc ions, along with conserved amino acid coordination for nucleophilic attack of the lactam ring to induce hydrolysis and inactivation of β-lactam and some carbapenem antibiotics. To this date there are no clinically relevant class B1 MBL inhibitors, however L-captopril has shown significant results against NDM-1, the most difficult MBL to inhibit. Herein, we report the synthesis and evaluation of novel nucleoside analogues modified with polyethylene glycolamino (PEGA) as potential inhibitors for class B1 MBLs. Molecular dynamics simulations, using internal coordinate mechanics (ICM) algorithm, were performed on subclass B1 enzyme complex models screened with twenty-one possible PEGA-nucleosides. Analogue A, 3'-deoxy-3'-(2-(2-hydroxyethoxy)ethanamino)-β-D-xylofuranosyluracil showed superior binding, with high specificity to the conserved zinc ions in the class B1 MBL active site by utilizing key β-lactam mimic points in the uridine nucleobase. The PEGA moiety showed chelating activity with zinc and disrupted the metal-binding amino acid geometry. In all subclass B1 proteins tested, analogue A had the most effective inhibition when compared to penicillin or L-captopril. Chemical synthesis was performed by condensation of the corresponding keto ribonucleoside with PEGA, followed by enantioselective reduction of the formed imine to produce the amino derivative with desired configuration. Pharmacokinetic and pharmacodynamic screenings revealed that PEGA-pyrimidine nucleosides are not toxic, nor violate Lipinski's rules. These results suggested that analogue A can be proposed as a potential metalloenzyme inhibitor against the widespread antibiotic resistant bacteria and is worth further in vitro and in vivo investigations.

Key taste components in two wild edible Boletus mushrooms using widely targeted metabolomics

Compounds from wild edible mushrooms has been reported to exert biological activities and contribute to the different flavors of mushrooms in our diet. Wild edible Boletus mushrooms are popular in Southwest China. In this study, we performed ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) based on widely targeted metabolomics analysis to identify key components. A total of 194 metabolites (113 upregulated, 81 downregulated) divided into 11 groups (49 metabolites in group lipids, 34 in amino acids and derivatives, 30 in organic acids, 18 in phenolic acids, 16 in nucleotides and derivatives, 13 in alkaloids, 6 in flavonoids, 3 in lignans and coumarins, 3 in tannins, 2 in terpenoids, and 20 in others) were found among Boletus bainiugan compared with B. subsplendidus. Through clustering analysis, principal component analysis (PCA), and orthogonal signal correction and partial least squares-discriminant analysis (OPLS-DA), different metabolites from fruiting bodies were clearly identified. Significant differences were observed in the metabolites between Boletus bainiugan and B. subsplendidus. These metabolites are involved in important biological functions. Our results provide new insights into important metabolites and theoretical basis for the taste difference of two wild edible Boletus mushrooms.

Targeted metabolomics in the cell culture media reveals increased uptake of branched amino acids by breast cancer cells

In addition to the altered amino acids in many cancer cells for their uncontrolled growth, targeted metabolomics in cell culture media could display a dynamic interaction between cancer cells and their micro-environments. Methodology for cell culture medium samples is different from that of cell lysates on sampling points, calculation and statistical analysis. Targeted profiling method of 40 amino acid and derivatives was validated and performed on cell culture medium samples from cell lines of HCC 1806 (breast cancer cell) and MCF-10A (normal breast epithelial cell). Different from the common up-regulation of amino acids in cancer cell lysates, significantly increased uptake (>2.5-fold, VIP>1 and p < 0.001) of branched amino acids was observed in the cell culture media from the breast cancer cells while acetylmethionine, cysteine-glutathione, glutathione, cysteine and glutamic acid were excreted significantly more by the cancer cells to their media. The characteristic metabolic changes of amino acid and derivatives in the cell culture media provide a dynamic portrayal for the interaction of the breast cancer cells, normal breast cells with their micro-environments, which helps to understand the underlying proliferation mechanism of breast cancer cells.

Secondary Metabolites of the Genus Amycolatopsis: Structures, Bioactivities and Biosynthesis.

Actinomycetes are regarded as important sources for the generation of various bioactive secondary metabolites with rich chemical and bioactive diversities. Amycolatopsis falls under the rare actinomycete genus with the potential to produce antibiotics. In this review, all literatures were searched in the Web of Science, Google Scholar and PubMed up to March 2021. The keywords used in the search strategy were “Amycolatopsis”, “secondary metabolite”, “new or novel compound”, “bioactivity”, “biosynthetic pathway” and “derivatives”. The objective in this review is to summarize the chemical structures and biological activities of secondary metabolites from the genus Amycolatopsis. A total of 159 compounds derived from 8 known and 18 unidentified species are summarized in this paper. These secondary metabolites are mainly categorized into polyphenols, linear polyketides, macrolides, macrolactams, thiazolyl peptides, cyclic peptides, glycopeptides, amide and amino derivatives, glycoside derivatives, enediyne derivatives and sesquiterpenes. Meanwhile, they mainly showed unique antimicrobial, anti-cancer, antioxidant, anti-hyperglycemic, and enzyme inhibition activities. In addition, the biosynthetic pathways of several potent bioactive compounds and derivatives are included and the prospect of the chemical substances obtained from Amycolatopsis is also discussed to provide ideas for their implementation in the field of therapeutics and drug discovery.

N‐Alkyl 3‐aminobut‐2‐enenitrile as a Non‐radioactive Side Product in Nucleophilic 18F‐Fluorination

AbstractWe found that acetonitrile acted as a reactant under the conventional reaction conditions for aliphatic nucleophilic 18F‐fluorination in acetonitrile to provide the N‐alkyl 3‐aminobut‐2‐enenitrile as one of the side products. Dimerization of acetonitrile promoted by a complex of K2CO3 and K222 provided 3‐aminobut‐2‐enenitrile, which acted as nucleophile to provide N‐alkyl amino derivatives. Based on the finding, avoiding acetonitrile in the drying of [18F]fluoride as well as 18F‐labeling enabled the preparation of 18F‐labeled compounds containing only a small amount of the corresponding alcohol. Finally, we used an automated synthesizer to achieve an efficient phase‐tag‐assisted synthesis of 18F‐labeled stilbene derivative as a 18F‐labeled amyloid‐β ligand.

Changes in the metabolic profile of human male postmortem frontal cortex and cerebrospinal fluid samples associated with heavy alcohol use.

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry-based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2-piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2-piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use.

Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53.

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

Altered metabolic and inflammatory transcriptomics after cardiac surgery in neonates with congenital heart disease

The study examines the whole blood transcriptome profile before and after cardiopulmonary bypass (CPB) in neonates with hypoplastic left heart syndrome (HLHS), a severe form of congenital heart disease, that can develop low cardiac output syndrome (LCOS). Whole blood mRNA transcriptome profiles of 13 neonates with HLHS before and after their first palliative surgery were analyzed to determine differentially expressed genes and pathways. The median age and weight at surgery were 4 days and 3.2 kg, respectively. Of the 13 patients, 8 developed LCOS. There was no significant difference between CPB, aortic cross clamp, deep hypothermic cardiac arrest times between patients that develop LCOS and those that do not. Upon comparing differential gene expression profiles between patients that develop LCOS and those that do not in pre-operative samples, 1 gene was up-regulated and 13 were down regulated. In the post-operative samples, 4 genes were up-regulated, and 4 genes were down regulated when patients that develop LCOS were compared to those that do not. When comparing post-operative samples to pre-operative samples in the patients that do not develop LCOS, 1484 genes were up-regulated, and 1388 genes were down regulated; while patients that developed LCOS had 2423 up-regulated genes, and 2414 down regulated genes for the same pre to post-operative comparison. Pathway analysis revealed differential regulation of inflammatory pathways (IL signaling, PDGF, NOTCH1, NGF, GPCR) and metabolic pathways (heme metabolism, oxidative phosphorylation, protein metabolism including amino acid and derivatives, fatty acid metabolism, TCA cycle and respiratory electron transport chain). By identifying altered transcriptome profiles related to inflammation and metabolism in neonates with HLHS who develop LCOS after CPB, this study opens for exploration novel pathways and potential therapeutic targets to improve outcomes in this high-risk population.

Regulation of aggregation-induced emission color of α-cyanostilbene luminogens through donor engineering of amino derivatives

In this contribution, α-cyanostilbene-based D-π-A-π-D type compounds consisting of different substituents on the amino donor group (e.g., fused, aryl/alkyl, and dialkyl) were designed, synthesized and their aggregation-induced emission was investigated thoroughly. The incorporation of these substituents furnished AIE features with tunable emission colors ranging from green-to-yellow-to-red. The compounds all showed a weak emission in THF; however, they showed an enhanced emission upon addition of water by forming emissive aggregates, which may arise from the restriction of twisted intramolecular charge transfer and E/Z isomerization. The DFT calculations revealed that the luminogens adopted distinctive conformations including a highly twisted one and a relatively coplanar one with the variation in the amino substituents.

Benzimidazole: A Multifacted Nucelus for Anticancer Agents

Cancer is characterized by an uncontrolled proliferation of cells, dedifferentiation, invasiveness and metastasis. Endothelial growth factor (eGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), Fibroblast growth factor (FGF), Vascular endothelial growth factor (VEGF), checkpoint kinase 1 &amp; 2 ( Chk1 &amp; Chk2), aurora kinases, topoisomerases, histone deacetylators (HDAC), poly(ADP-Ribose)polymerase (PARP), farnesyl transferases, RAS-MAPK pathway and PI3K-Akt-mTOR pathway, are some of the prominent mediators implicated in the proliferation of tumor cells. Huge artillery of natural and synthetic compounds as anticancer, which act by inhibiting one or more of the enzymes and/or pathways responsible for the progression of tumor cells, is reported in the literature. The major limitations of anticancer agents used in clinics as well as of those under development in literature are normal cell toxicity and other side effects due to lack of specificity. Hence, medicinal chemists across the globe have been working for decades to develop potent and safe anticancer agents from natural sources as well as from different classes of heterocycles. Benzimidazole is one of the most important and explored heteronucelus because of their versatility in biological actions as well as synthetic applications in medicinal chemistry. The structural similarity of amino derivatives of benzimidazole with purines makes it a fascinating nucleus for the development of anticancer, antimicrobial and anti-HIV agents. This review article is an attempt to critically analyze various reports on benzimidazole derivatives acting on different targets to act as anticancer so as to understand the structural requirements around benzimidazole nucleus for each target and enable medicinal chemists to promote rational development of antitumor agents.

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity.

Amino- and polyaminophthalazinones were synthesized by the palladium‐catalyzed amination (alkyl- and arylamines, polyamines) of 4-bromophthalazinones in good yields. The coordinating properties of selected aminophthalazinones towards Cu(II) ions were investigated and the participation of the nitrogen atoms in the complexation of the metal ion was shown. A biological screening of the potential cytotoxicity of selected synthesized compounds on HT-29 and PC-3 cell lines, as well as on the L-929 cell line, proved that some amino derivatives of phthalazinone show interesting anticancer activities. The detailed synthesis, spectroscopic data, and biological assays are reported.

Gene Set Enrichment Analysis of Interaction Networks Weighted by Node Centrality.

Gene set enrichment analysis (GSEA) is a powerful tool to associate a disease phenotype to a group of genes/proteins. GSEA attributes a specific weight to each gene/protein in the input list that depends on a metric of choice, which is usually represented by quantitative expression data. However, expression data are not always available. Here, GSEA based on betweenness centrality of a protein–protein interaction (PPI) network is described and applied to two cases, where an expression metric is missing. First, personalized PPI networks were generated from genes displaying alterations (assessed by array comparative genomic hybridization and whole exome sequencing) in four probands bearing a 16p13.11 microdeletion in common and several other point variants. Patients showed disease phenotypes linked to neurodevelopment. All networks were assembled around a cluster of first interactors of altered genes with high betweenness centrality. All four clusters included genes known to be involved in neurodevelopmental disorders with different centrality. Moreover, the GSEA results pointed out to the evidence of “cell cycle” among enriched pathways. Second, a large interaction network obtained by merging proteomics studies on three neurodegenerative disorders was analyzed from the topological point of view. We observed that most central proteins are often linked to Parkinson’s disease. The selection of these proteins improved the specificity of GSEA, with “Metabolism of amino acids and derivatives” and “Cellular response to stress or external stimuli” as top-ranked enriched pathways. In conclusion, betweenness centrality revealed to be a suitable metric for GSEA. Thus, centrality-based GSEA represents an opportunity for precision medicine and network medicine.