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A Mechanistic Study on the Non-enzymatic Hydrolysis of Kdn Glycosides
Sialic acids are biologically important carbohydrates that are prevalent throughout nature. We are interested in their intrinsic reactivity in aqueous solution and how such reactivity affects the design of substrates for investigation of enzymes that process these sugars. To probe the reactivity differences between two sialic acid family members N-acetylneuraminic acid and Kdn we measured the rate constants for hydrolysis of 4-nitrophenyl 3-deoxy-d-glycero-α-d-galacto-non-2-ulosonide in aqueous solution. The kinetic data is consistent with glycosidic C?O bond cleavage occurring via four mechanistic pathways, and these are: (i) hydronium ion-catalyzed hydrolysis of the neutral sugar; (ii) hydronium ion-catalyzed hydrolysis of the glycosidic carboxylate; (iii) water-catalyzed hydrolysis of the anionic glycoside; and (iv) base-promoted reaction of the anionic glycoside. To study the effects of C-5 substitution on the Kdn glycoside we made 4-nitrophenyl 5-O-methyl-α-Kdn glycoside and determined its rate constants for hydrolysis. All hydrolytic rate constants for both Kdn glycosides were larger than those reported for the parent N-acetyl-α-neuraminide. The water-catalyzed reaction (pathway iii) exhibited a βlg value of ?1.3±0.1. We conclude that the larger rate constants associated with C5-oxygen containing sialosides results from less steric congestion at the hydrolytic transition states than for the parent C-5 acetamido glycoside.
Bennet, Andrew J.,Colombo, Cinzia,Hakak-Zargar, Benyamin,Nejatie, Ali
supporting information

(2022/01/13)

Prostate-Specific Membrane Antigen-Targeted Turn-on Probe for Imaging Cargo Release in Prostate Cancer Cells
The tunable nature of phosphoramidate linkers enables broad applicability as pH-triggered controlled-release platforms, particularly in the context of antibody-and small-molecule-drug conjugates (ADCs and SMDCs), where there remains a need for new linker technology. Herein, we explored in-depth the release of turn-on fluorogenic payloads from a homoserinyl-based phosphoramidate acid-cleavable linker. Kinetics of payload release from the scaffold was observed in buffers representing the pH conditions of systemic circulation, early and late endosomes, and lysosomes. It was found that payload release takes place in two key consecutive steps: (1) P-N bond hydrolysis and (2) spacer immolation. These two steps were found to follow pseudo-first-order kinetics and had opposite dependencies on pH. P-N bond hydrolysis increased with decreasing pH, while spacer immolation was most rapid at physiological pH. Despite the contrasting release kinetics of these two steps, maximal payload release was observed at the mildly acidic pH (5.0-5.5), while minimal payload release occurred at physiological pH. We integrated this phosphoramidate-payload linker system into a PSMA-targeted fluorescent turn-on probe to study the intracellular trafficking and release of a fluorescent payload in PSMA-expressing prostate cancer cells. Results showed excellent turn-on and accumulation of the coumarin payload in the late endosomal and lysosomal compartments of these cells. The release properties of this linker mark it as an attractive alternative in the modular design of ADCs and SMDCs, which demand selective intracellular payload release triggered by the pH changes that accompany intracellular trafficking.
Abbasi, Armina,Berkman, Clifford E.,Caromile, Leslie A.,Lovingier, Christine L.,Mesbahi, Nooshin,Olatunji, Feyisola P.,Panteah, Mylan,Savoy, Emily A.,Talley, Cresencia M.
p. 2386 - 2396
(2021/11/16)

B(C6F5)3-catalyzed synthesis of coumarins via Pechmann condensation under solvent-free conditions
Tris(pentafluorophenyl)borane [B(C6F5)3] catalyzed simple, efficient and environmentally benign protocol has been developed for the Pechmann condensation using variety of phenols and β-ketoesters under solvent-free conditions to afford coumarin derivatives. The present protocol displayed significant advantages such as low catalyst loading, short reaction time, mild reaction conditions, low toxicity, easy work-up, high yields, and compatibility with other functional groups. In addition, it is a convenient, clean, and fast alternative approach for synthesizing variety of coumarin derivatives. Moreover, the applicability of this method towards large-scale synthesis demonstrated its suitability for the industrial application. Graphic abstract: [Figure not available: see fulltext.]
Prajapti, Santosh Kumar,Rao, S. Prakash
p. 469 - 473
(2021/03/26)

Nanostructured coumarin-based cobalt complex as an efficient, heterogeneous and recyclable catalyst for the three-component synthesis of benzo[b]pyran and 3,4-dihydropyrano[c]chromene derivatives
Abstract: An improved one-pot three-component reaction of carbonyl compounds (dimedon, 4-hydroxy coumarin and 1,3-cyclohexadion) with malononitrile and aryl aldehydes in aqueous media (H2O:EtOH) as a solvent with short reaction time for the synthesis of benzo[b]pyran and 3,4- dihydropyrano[c]chromane derivatives by using nanostructured coumarin-based cobalt complex as an efficient heterogeneous catalyst. The salient features of this new protocol include simple procedure, high yields, easy isolation of products without need to column chromatography and short reaction times. Also, the nanocatalyst was recovered by adding EtOH and reused five times without significant loss of its catalytic activity. Biological impact assessments of the complex were conducted by DNA cleavage ability assay and eukaryotic cell toxicity measurement. Although the complex showed single-strand DNA breakage under oxidative conditions, its high polar nature revealed a marked decrease in cell toxicity data due to the restriction on cell entry. Graphic abstract: [Figure not available: see fulltext.]
Sharghi, Hashem,Razavi, Seyyede Faeze,Aberi, Mahdi,Sabzalizadeh, Fatemeh,Karbalaei-Heidari, Hamid Reza
p. 1641 - 1655
(2021/01/09)

One-Pot Three-Component Synthesis of 2,4,5-Triaryl-1H-imidazoles Using Mn2+Complex of [7-Hydroxy-4-methyl-8-coumarinyl] Glycine as a Heterogeneous Catalyst
A highly efficient and simple synthesis of 2,4,5-trisubstituted imidazoles has been developed using highly reusable support‐free Mn2+complex of [7-hydroxy-4-methyl-8-coumarinyl] glycine as a heterogeneous catalyst via a one-pot three-component reaction of benzil, aldehydes and ammonium acetate as a nitrogen source. Moreover, this catalyst was characterized by various techniques such as field emission scanning electron microscope (FE-SEM), energy dispersive X-ray spectroscopy (EDX), FT-IR spectroscopy, powder X-ray diffraction (XRD), inductively coupled plasma (ICP) and thermal gravimetric analysis (TGA). Also, the catalyst is stable and could be reused for at least six times without significant loss of activity. Graphic Abstract: [Figure not available: see fulltext.]
Aberi, Mahdi,Razavi, Seyyede Faeze,Sharghi, Hashem
(2021/08/16)

Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads
Polyketide synthase 13 (Pks13) is an essential enzyme in the synthesis of mycolic acids in Mtb. Therefore, Pks13 is a promising drug target for tuberculosis treatment. We used a structure-guided approach to identify novel chemotype inhibitors of Pks13 and assessed them using a Pks13 enzymatic assay and surface plasmon resonance. The structure–activity relationships (SAR) results demonstrated that the substituents at the 2, 5, and 6 positions of the 4H-chromen-4-one scaffold are critical for maintaining the MIC. Compound 6e with 2-hydroxyphenyl at the 2 position of the 4H-chromen-4-one scaffold, exhibited potent activity against Mtb H37Rv (MIC = 0.45 μg/mL) and displayed good Pks13 affinity and inhibition (IC50 = 14.3 μM). This study described here could provide an avenue to explore a novel inhibitor class for Pks13 and aid the further development of antituberculosis drugs.
Wang, Xiao,Zhao, Wenting,Wang, Bin,Ding, Wei,Guo, Hao,Zhao, Hongyi,Meng, Jianzhou,Liu, Sihan,Lu, Yu,Liu, Yishuang,Zhang, Dongfeng
(2021/06/30)

Alpha-L-fucosidase detection probe and preparation method and application thereof
The invention discloses an alpha-L-fucosidase detection probe. The structural general formula of the probe is shown in the specification, wherein in the formula I, R1 is an acetyl-protected monosaccharidyl or monosaccharidyl group; and R2 is a pyranonitrile group or a benzopyran nitrile group. The alpha-L-fucosidase detection probe prepared by the invention improves the detection sensitivity, can detect serum AFU with high selectivity, and can be used for kits or drugs for positioning and detecting cancer cells.
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Paragraph 0061-0063

(2021/04/10)

A Cationic Micelle as In Vivo Catalyst for Tumor-Localized Cleavage Chemistry
The emerging strategies of accelerating the cleavage reaction in tumors through locally enriching the reactants is promising. Yet, the applications are limited due to the lack of the tumor-selectivity for most of the reactants. Here we explored an alternative approach to leverage the rate constant by locally inducing an in vivo catalyst. We found that the desilylation-induced cleavage chemistry could be catalyzed in vivo by cationic micelles, and accelerated over 1400-fold under physiological condition. This micelle-catalyzed controlled release platform is demonstrated by the release of a 6-hydroxyl-quinoline-2-benzothiazole derivative (HQB) in two cancer cell lines and a NIR dye in mouse tumor xenografts. Through intravenous injection of a pH-sensitive polymer micelles, we successfully applied this strategy to a prodrug activation of hydroxyl camptothecin (OH-CPT) in tumors. Its “decaging” efficiency is 42-fold to that without cationic micelles-mediated catalysis. This micelle-catalyzed desilylation strategy unveils the potential that micelle may act beyond a carrier but a catalyst for local perturbing or activation.
Chen, Mengqi,Ding, Zexuan,Hong, Hanyu,Li, Zi-Chen,Liu, Zhibo,Qi, Jianyuan,Rui, Yuchen,Wang, Chunhong
supporting information
p. 19750 - 19758
(2021/07/12)

Hymecromone naphthoquinone ethers as probes for hydrogen sulfide detection
Hydrogen sulfide (H2S), as one of the important gasotransmitters, plays an essential role in a many physiological and pathological processes. Commonly used methods for real-time detection and quantification of H2S are rather complicated. This report presents a simple fluorescence and colorimetry dual-mode assay based on ethers (Nq-Cm and Nq-2Cm) derived from hymecromone (7-hydroxy-4-methylcoumarin, Cm) and naphthoquinone (Nq). In these compounds an electron-deficient naphthoquinone unit was used as a suitable reagent for nucleophilic aromatic substitution (SNAr) reaction. Thiolysis of Nq-Cm and Nq-2Cm at physiological pH releases Cm and causes an significant fluorescence enhancement at 448 nm (with excitation at 320 nm). At the same time, the resulting naphthoquinone derivative Nq-2SH causes the solution a purple color, which allows naked-eye detection. Thus Nq-Cm and Nq-2Cm are colorimetrically selective for H2S. The efficacy of the Nq-Cm and Nq-2Cm were demonstrated in buffer with associated submicromolar detection limit as low as 130 nM and 150 nM, respectively. Presented results suggest that both probes are excellent quantitative detection tool for H2S.
?wierczyńska, Ma?gorzata,Grzelakowska, Aleksandra,Kolińska, Jolanta,Podsiad?y, Rados?aw,Romański, Jaros?aw,S?owiński, Daniel,Szala, Marcin
(2021/09/04)

Enzyme Catalysis in Non-Native Environment with Unnatural Selectivity Using Polymeric Nanoreactors
The utilization of enzymes for catalysis in organic solvents, while exhibiting selectivity to different substrates, is a big challenge. We report an amphiphilic random copolymer system that self-assembles with enzymes in an organic solvent to form nanoreactors. These encapsulated enzymes are not denatured and they do preserve the catalytic activity. The cross-linkable functional groups in the hydrophobic compartments of the polymers offer to control accessibility to the enzyme. This varied accessibility due to the polymer host, rather than the enzyme itself, endows the nanoreactor with an unnatural selectivity. The findings here highlight the significant potential of simple polymer-based enzyme nanoreactors to execute selective organic reactions under non-native conditions.
Gao, Jingjing,Le, Stephanie,Thayumanavan, S.
supporting information
p. 27189 - 27194
(2021/11/18)

Evaluation of borinic acids as new, fast hydrogen peroxide–responsive triggers
Hydrogen peroxide (H2O2) is responsible for numerous damages when overproduced, and its detection is crucial for a better understanding of H2O2-mediated signaling in physiological and pathological processes. For this purpose, various “off–on” small fluorescent probes relying on a boronate trigger have been prepared, and this design has also been involved in the development of H2O2-activated prodrugs or theranostic tools. However, this design suffers from slow kinetics, preventing activation by H2O2 with a short response time. Therefore, faster H2O2-reactive groups are awaited. To address this issue, we have successfully developed and characterized a prototypic borinic-based fluorescent probe containing a coumarin scaffold. We determined its in vitro kinetic constants toward H2O2-promoted oxidation. We measured 1.9 × 104 M-1·S-1 as a second-order rate constant, which is 10,000-fold faster than its well-established boronic counterpart (1.8 M-1·S-1). This improved reactivity was also effective in a cellular context, rendering borinic acids an advantageous trigger for H2O2-mediated release of effectors such as fluorescent moieties.
Gatin-Fraudet, Blaise,Ottenwelter, Roxane,Le Saux, Thomas,Norsikian, Stéphanie,Pucher, Mathilde,Lombès, Thomas,Baron, Aurélie,Durand, Philippe,Doisneau, Gilles,Bourdreux, Yann,Iorga, Bogdan I.,Erard, Marie,Jullien, Ludovic,Guianvarc’h, Dominique,Urban, Dominique,Vauzeilles, Boris
(2021/12/23)

A ratiometric fluorescent probe for the detection of β-galactosidase and its application
Herein, a coumarin fluorescent probe (Probe1) was developed for the ratiometric detection of β-galactosidase (β-gal) activity. The detection range was 0-0.1 U mL?1and 0.2-0.8 U mL?1, and the limit of detection (LOD) was 0.0054 U mL?1. Moreover, the luminous intensity of Probe1increased gradually with increase in β-gal activity. It could be observed under 254 nm UV irradiation by the naked eye. Furthermore, this method only required a small amount of sample (20 μL) and a short analytical time (30 min) for the detection of β-gal activity with a low LOD. Probe1was successfully used to detect β-gal activity in real fruit samples, and can be applied to the quantitative and qualitative detection of β-gal activity.
Li, Yanan,Deng, Bing,Chen, Haitao,Yang, Shaoxiang,Sun, Baoguo
p. 13341 - 13347
(2021/04/22)

Peroxide-responsive boronate ester-coupled turn-on fluorogenic probes: Direct linkers supersede self-immolative linkers for sensing peroxides
Turn-on fluorogenic probes are commonly utilized for an efficient estimation of reactive oxygen species such as H2O2. In the present study, three different sets of turn-on fluorogenic probes for sensing H2O2 wer
Sufian, Abu,Bhattacherjee, Debojit,Mishra, Tripti,Bhabak, Krishna P.
(2021/04/19)

A Visible-Light Promoted Amine Oxidation Catalyzed by a Cp*Ir Complex
Through a rapid screening of Cp*Ir complexes based on a turn-on type fluorescence readout, a [Cp*Ir(dipyrido[3,2-a : 2’,3’-c]phenazine)Cl]+ complex was found to catalyze the blue-light promoted dehydrogenation of N-heterocycles under physiological conditions. In the dehydrogenation of tetrahydroisoquinolines, the catalyst preferentially yielded the monodehydrogenated product, accompanying H2O2 generation. We surmise that this mechanism may be reminiscent of flavin-dependent oxidases.
Davis, Holly Jane,H?ussinger, Daniel,Ward, Thomas R.,Okamoto, Yasunori
p. 4512 - 4516
(2020/07/27)

The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites
Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets. Using a probe analog of the antimalarial natural product Sal A, Yoo et al. identify its targets as multiple essential serine hydrolases, including a homolog of human monoacylglycerol lipase. Because parasites were unable to generate robust in vitro resistance to Sal A, these enzymes represent promising targets for antimalarial drugs.
Bogyo, Matthew,Boucher, Michael J.,Cieplak, Piotr,Fidock, David A.,Foe, Ian T.,Gn?dig, Nina F.,Kumpornsin, Krittikorn,Kurita, Kenji,Lee, Marcus C. S.,Linington, Roger G.,Long, Jonathan Z.,Mok, Sachel,Onguka, Ouma,Schulze, Christopher J.,Stokes, Barbara H.,Terrell, Stephanie M.,Uhlemann, Anne-Catrin,Weerapana, Eranthie,Yeo, Tomas,Yoo, Euna,Zhou, Yani
p. 143 - 157
(2020/02/18)

METHODS AND COMPOSITIONS FOR INCREASING THE ACTIVITY IN THE CNS OF HEXOSAMINIDASE A, ACID SPHINGOMYELINASE, AND PALMITOYL-PROTEIN THIOESTERASE 1
Provided herein are methods and compositions for treating a subject suffering from an enzyme deficiency in the central nervous system (CNS). The bifunctional fusion antibody provided herein comprise an antibody to an endogenous blood brain barrier (BBB) receptor and an enzyme deficient in Tay Sachs disease (TSD), Nieman Pick Disease (NPD), or Neuronal Ceroid Lipofuscinosis 1 (NCL1), which are caused by mutations in the respective lysosomal enzymes, hexosaminidase A (HEXA), acid sphingomyelinase (ASM), and palmitoyl-protein thioesterase 1 (PPT1). The fusion antibodies provided herein comprise HEXA, ASM, and PPT1. The methods of treating an enzyme deficiency in the CNS comprise systemic administration of a fusion antibody provided herein.
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Paragraph 0070; 00194-00195; 00207

(2020/03/02)

General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation in Vivo
Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.
Sun, Tao,Lv, Tian,Wu, Jianbing,Zhu, Mingchao,Fei, Yue,Zhu, Jie,Zhang, Yihua,Huang, Zhangjian
p. 13899 - 13912
(2020/12/02)

Non-enzymatic protein acetylation by 7-acetoxy-4-methylcoumarin: Implications in protein biochemistry
Background: The semi-synthetic acetoxycoumarins are known to acetylate proteins using novel enzymatic Calreticulin Transacetylase (CRTAase) system in cells. However, the non-enzymatic protein acetylation by polyphenolic acetates is not known. Objective: To investigate the ability of 7-acetoxy-4-methyl coumarin (7-AMC) to acetylate proteins non-enzymatically in the test tube. Methods: We incubated 7-AMC with BSA and analyzed the protein acetylation using Western blot technique. Further, BSA induced biophysical changes in the spectroscopic properties of 7-AMC was analyzed using Fluorescence spectroscopy. Results: Using pan anti-acetyl lysine antibody, herein we demonstrate that 7-AMC acetylates Bovine Serum Albumin (BSA) in time and concentration dependent manner in the absence of any enzyme. 7-AMC is a relatively less fluorescent molecule compared to the parental compound, 7-hydroxy-4-methylcoumarin (7-HMC), however the fluorescence of 7-AMC increased by two fold on incubation with BSA, depending on the time of incubation and concentration of BSA. Analysis of the reaction mixture of 7-AMC and BSA after filtration revealed that the increased fluorescence is associated with the compound of lower molecular weight in the filtrate and not residual BSA, suggesting that the less fluorescent 7-AMC undergoes self-hydrolysis in the presence of protein to give highly fluorescent parental molecule 7-HMC and acetate ion in polar solvent (phosphate buffered saline, PBS). The protein augmented conversion of 7-AMC to 7-HMC was found to be linearly related to the protein concentration. Conclusion: Thus protein acetylation induced by 7-AMC could also be non-enzymatic in nature and this molecule can be exploited for quantification of proteins.
Bhatt, Anant Narayan,Rai, Yogesh,Verma, Amit,Pandey, Sanjay,Kaushik, Kumar,Parmar, Virinder S.,Arya, Anu,Prasad, Ashok K.,Dwarakanath, Bilikere S.
p. 736 - 743
(2020/10/02)

Single-Molecule Analysis Determines Isozymes of Human Alkaline Phosphatase in Serum
Alkaline phosphatase (ALP) is an important biomarker, as high levels of ALP in blood can indicate liver disease or bone disorders. However, current clinical blood tests only measure the total concentration of ALP but are unable to distinguish enzyme isotypes. Here, we demonstrate a novel and rapid approach to profile various ALP isozymes in blood via a single-molecule-analysis platform. The microarray platform provides enzyme kinetics of hundreds of individual molecules at high throughput. Using these single molecule kinetics, we characterize the different activity profiles of ALP isotypes. By analyzing both healthy and disease samples, we found the single molecule activity distribution of ALP in serum reflects the health status of patients. This result demonstrates the potential utility of the method for improving the conventional ALP test, as well as for analyzing other enzymatic biomarkers, including enzyme isotypes.
Jiang, Yu,Li, Xiang,Walt, David R.
supporting information
p. 18010 - 18015
(2020/08/19)

The phosphatase-like activity of zirconium oxide nanoparticles and their application in near-infrared intracellular imaging
In this study, the phosphatase mimetic activity of zirconium oxide nanoparticles (ZrO2NPs) has been demonstrated. They can effectively catalyze the dephosphorylation of a series of commercial fluorogenic and chromogenic substrates of natural phosphatases. Compared with natural phosphatases, ZrO2NPs possess several advantages such as low cost, facile preparation procedures, and high stability in a broader pH range or at high temperatures. In addition, the activity of ZrO2NPs toward some important biomolecules was investigated. The ZrO2NPs can catalyze the dephosphorylation of ATP ando-phospho-l-tyrosine, but they cannot react with DNA strands. These data are important for the further bio-related applications of ZrO2NPs. Finally, the potential application of ZrO2NPs in intracellular imaging is also demonstrated by using a near-infrared fluorescent substrate of alkaline phosphatase.
Hu, Lianzhe,Hu, Xilu,Huang, Ting,Liao, Hong,Wang, Min
supporting information
p. 4428 - 4433
(2020/06/03)

Indolizines Enabling Rapid Uncaging of Alcohols and Carboxylic Acids by Red Light-Induced Photooxidation
The irradiation of red light-emitting-diode light (λ = 660 nm) to 3-acyl-2-methoxyindolizines in the presence of a catalytic amount of methylene blue triggered the photooxidation of the indolizine ring, resulting in a nearly quantitative release of alcohols or carboxylic acids within a few minutes. The method was applicable for photouncaging various functional molecules such as a carboxylic anticancer drug and a phenolic fluorescent dye from the corresponding indolizine conjugates, including an insulin-indolizine-dye conjugate.
Watanabe, Kenji,Terao, Nodoka,Kii, Isao,Nakagawa, Reiko,Niwa, Takashi,Hosoya, Takamitsu
supporting information
p. 5434 - 5438
(2020/07/24)

Synthesis and biological screening of thiosemicarbazones of substituted 3-acetylcoumarins having D-glucose moiety
Thiosemicarbazones 5a-j were synthesized with yields of 45–68% by condensation of 3-acetylcoumarins 3a-j and tetra-O-acetyl-β-D-thiosemicarbazide 4. All obtained thiosemicarbazones were screened for anti-microorganic activities against bacteria (B. subtilis, S. aureus, S. epidermidis, E. coli, P. aeruginosa, K. pneumoniae, S. typhimurium) and fungi (A. niger, C. albicans, S. cerevisiae, and A. flavus). Some compounds had significant inhibitory activity with MICs of 0.78–3.125 μM in comparison with 5a, including 5e,h,i for S. aureus, and 5c,f,i for S. epidermidis (Gram-(+) bacteria), 5c,f,g for E.coli, 5f for K. pneumoniae, 5b,c,g for P. aeruginosa, and 5i for S. typhimurium (Gram-(?) bacteria), 5d,h,i for A. niger, 5i for A. flavus, 5b,d,e,h for C. albicans, and 5i for S. cerevisiae. Compounds exhibited excellent activity against tested microorganism with MIC = 0.78 μM, including 5h,i (against S. aureus), 5h (against C. albicans), and 5i (against S. cerevisiae).
Ngoc Toan, Vu,Dinh Thanh, Nguyen,Minh Tri, Nguyen,Thi Thu Huong, Nguyen
supporting information

(2020/11/20)

Concise synthesis of sulfoquinovose and sulfoquinovosyl diacylglycerides, and development of a fluorogenic substrate for sulfoquinovosidases
The sulfolipid sulfoquinovosyl diacylglycerol (SQDG) and its headgroup, the sulfosugar sulfoquinovose (SQ), are estimated to harbour up to half of all organosulfur in the biosphere. SQ is liberated from SQDG and related glycosides by the action of sulfoquinovosidases (SQases). We report a 10-step synthesis of SQDG that we apply to the preparation of saturated and unsaturated lipoforms. We also report an expeditious synthesis of SQ and (13C6)SQ, and X-ray crystal structures of sodium and potassium salts of SQ. Finally, we report the synthesis of a fluorogenic SQase substrate, methylumbelliferyl α-d-sulfoquinovoside, and examination of its cleavage kinetics by two recombinant SQases. These compounds will assist in dissecting the role of sulfoglycolysis in the biogeochemical sulfur cycle and understanding the molecular basis of sulfoglycolysis.
Zhang, Yunyang,Mui, Janice W.-Y.,Arumaperuma, Thimali,Lingford, James P.,Goddard-Borger, Ethan D.,White, Jonathan M.,Williams, Spencer J.
p. 675 - 686
(2020/02/11)

Single-Chain Nanoparticle Delivers a Partner Enzyme for Concurrent and Tandem Catalysis in Cells
Combining synthetic chemistry and biocatalysis is a promising but underexplored approach to intracellular catalysis. We report a strategy to codeliver a single-chain nanoparticle (SCNP) catalyst and an exogenous enzyme into cells for performing bioorthogonal reactions. The nanoparticle and enzyme reside in endosomes, creating engineered artificial organelles that manufacture organic compounds intracellularly. This system operates in both concurrent and tandem reaction modes to generate fluorophores or bioactive agents. The combination of SCNP and enzymatic catalysts provides a versatile tool for intracellular organic synthesis with applications in chemical biology.
Chen, Junfeng,Li, Ke,Shon, Ji Seon,Zimmerman, Steven C.
supporting information
p. 4565 - 4569
(2020/04/01)

Synthesis of 6- and 7-alkoxy-4-methylcoumarins from corresponding hydroxy coumarins and their conversion into 6- and 7-alkoxy-4-formylcoumarin derivatives
Hydroxy derivatives of 4-methyl-2H-chromen-2-one were prepared from hydroquinone and resorcinol through their reaction with ethyl acetoacetate. These hydroxy coumarins were then converted into corresponding alkoxy derivatives by reaction with alkyl halides. The yields of 6- and 7-alkoxy-4-methylcoumarins 3a–i and 4a–i were 55?95%. Oxidation of these compounds by selenium dioxide under conventional and microwave-assisted heating conditions produced corresponding 4-formyl compounds 5b–h and 6b–h with yields of 40?67% and 90?93%, respectively. Several 6- and 7-alkoxy-4-methylcoumarins 3a–i, 4a–i and nearly all 6- and 7-alkoxy-4-formylcoumarins 5b–h, 6b–h are novel compounds.
Ngoc Toan, Vu,Dinh Thanh, Nguyen
p. 3603 - 3615
(2020/08/21)

A fast, miniaturised in-vitro assay developed for quantification of lipase enzyme activity
The discovery of allosteric modulators is a multi-disciplinary approach, which is time- and cost-intensive. High-throughput screening combined with novel computational tools can reduce these factors. Thus, we developed an enzyme activity assay, which can be included in the drug discovery work-flow subsequent to the in-silico library screening. While the in-silico screening yields in the identification of potential allosteric modulators, the developed in-vitro assay allows for the characterisation of them. Candida rugosa lipase (CRL), a glyceride hydrolysing enzyme, has been selected for the pilot development. The assay conditions were adjusted to CRL’s properties including pH, temperature and substrate specificity for two different substrates. The optimised assay conditions were validated and were used to characterise Tropolone, which was identified as an allosteric modulator. In conclusion, the assay is a reliable, reproducible, and robust tool, which can be streamlined with in-silico screening and incorporated in an automated high-throughput screening workflow.
Menden, Ariane,Hall, Davane,Paris, Daniel,Mathura, Venkatarian,Crawford, Fiona,Mullan, Michael,Crynen, Stefan,Ait-Ghezala, Ghania
p. 1474 - 1480
(2019/08/26)

A High-Throughput Glycosyltransferase Inhibition Assay for Identifying Molecules Targeting Fucosylation in Cancer Cell-Surface Modification
In cancers, increased fucosylation (attachment of fucose sugar residues) on cell-surface glycans, resulting from the abnormal upregulation of the expression of specific fucosyltransferase enzymes (FUTs), is one of the most important types of glycan modifications associated with malignancy. Fucosylated glycans on cell surfaces are involved in a multitude of cellular interactions and signal regulation in normal biological processes, as well as in disease. For example, sialyl LewisX is a fucosylated cell-surface glycan that is abnormally abundant in some cancers where it has been implicated in facilitating metastasis, allowing circulating tumor cells to bind to the epithelial tissue within blood vessels and invade into secondary sites by taking advantage of glycan-mediated interactions. To identify inhibitors of FUT enzymes as potential cancer therapeutics, we have developed a novel high-throughput assay that makes use of a fluorogenically labeled oligosaccharide as a probe of fucosylation. This probe, which consists of a 4-methylumbelliferyl glycoside, is recognized and hydrolyzed by specific glycoside hydrolase enzymes to release fluorescent 4-methylumbelliferone, yet when the probe is fucosylated prior to treatment with the glycoside hydrolases, hydrolysis does not occur and no fluorescent signal is produced. We have demonstrated that this assay can be used to measure the inhibition of FUT enzymes by small molecules, because blocking fucosylation will allow glycosidase-catalyzed hydrolysis of the labeled oligosaccharide to produce a fluorescent signal. Employing this assay, we have screened a focused library of small molecules for inhibitors of a human FUT enzyme involved in the synthesis of sialyl LewisX and demonstrated that our approach can be used to identify potent FUT inhibitors from compound libraries in microtiter plate format.
Zhang, Xiaohua,Chen, Fei,Petrella, Alessandro,Chacón-Huete, Franklin,Covone, Jason,Tsai, Teng-Wei,Yu, Ching-Ching,Forgione, Pat,Kwan, David H.
p. 715 - 724
(2019/03/26)

A fluorescence-based activity assay for immobilized lipases in non-native media
A new method for the analysis of lipase activity in the immobilized state is developed. The fluorescence assay aims to quantify the potential of lipases for the application in organic solvents. As lipases are universally immobilized on polymeric carriers for the use in bioorganic synthesis, the assay includes an immobilization step on the walls of polymeric cuvettes. The activity of the immobilized lipase is probed by 4-methylumbelliferyl ester hydrolysis. The activity retention as a function of solvent concentration is used as a measure for the solvent resistance of the enzyme variant. The method is applied to two different lipases, Candida antarctica lipase B (CalB) and Bacillus subtilis lipase A (BSLA) in the presence of the solvents acetonitrile and ethanol. By comparison of the assay results with a commercial biocatalyst consisting of CalB on polymeric carrier (Novozyme 435) it is demonstrated that the assay allows a good prediction of the activity of the respective lipase as immobilisate on polymeric carriers. The assay surpasses the respective analysis in solution in terms of accuracy and precision.
Ingenbosch, Kim N.,Rousek, Anna,Wunschik, Dennis S.,Hoffmann-Jacobsen, Kerstin
p. 22 - 27
(2019/01/30)

Chloromethyl-modified Ru(ii) complexes enabling large pH jumps at low concentrations through photoinduced hydrolysis
Photoacid generators (PAGs) are finding increasing applications in spatial and temporal modulation of biological events in vitro and in vivo. In these applications, large pH jumps at low PAG concentrations are of great importance to achieve maximal expected manipulation but minimal unwanted interference. To this end, both high photoacid quantum yield and capacity are essential, where the capacity refers to the proton number that a PAG molecule can release. Up to now, most PAGs only produce one proton for each molecule. In this work, the hydrolysis reaction of benzyl chlorides was successfully leveraged to develop a novel type of PAG. Upon visible light irradiation, Ru(ii) polypyridyl complexes modified with chloromethyl groups can undergo full hydrolysis with photoacid quantum yield as high as 0.6. Depending on the number of the chloromethyl groups, the examined Ru(ii) complexes can release multiple protons per molecule, leading to large pH jumps at very low PAG concentrations, a feature particularly favorable for bio-related applications.
Tian, Na,Sun, Weize,Feng, Yang,Guo, Xusheng,Lu, Jian,Li, Chao,Hou, Yuanjun,Wang, Xuesong,Zhou, Qianxiong
p. 9949 - 9953
(2019/11/16)

Comprehensive kinetic and substrate specificity analysis of an arylsulfatase from Helix pomatia using mass spectrometry
Sulfatases hydrolyze sulfated metabolites to their corresponding alcohols and are present in all domains of life. These enzymes have found major application in metabolic investigation of drugs, doping control analysis and recently in metabolomics. Interest in sulfatases has increased due to a link between metabolic processes involving sulfated metabolites and pathophysiological conditions in humans. Herein, we present the first comprehensive substrate specificity and kinetic analysis of the most commonly used arylsulfatase extracted from the snail Helix pomatia. In the past, this enzyme has been used in the form of a crude mixture of enzymes, however, recently we have purified this sulfatase for a new application in metabolomics-driven discovery of sulfated metabolites. To evaluate the substrate specificity of this promiscuous sulfatase, we have synthesized a series of new sulfated metabolites of diverse structure and employed a mass spectrometric assay for kinetic substrate hydrolysis evaluation. Our analysis of the purified enzyme revealed that the sulfatase has a strong preference for metabolites with a bi- or tricyclic aromatic scaffold and to a lesser extent for monocyclic aromatic phenols. This metabolite library and mass spectrometric method can be applied for the characterization of other sulfatases from humans and gut microbiota to investigate their involvement in disease development.
Correia, Mário S.P.,Ballet, Caroline,Meistermann, Hannes,Conway, Louis P.,Globisch, Daniel
p. 955 - 962
(2019/02/09)

Evaluation of droplet-based microfluidic platforms as a convenient tool for lipases and esterases assays
The accurate estimation of kinetic parameters is of fundamental importance for biochemical studies for research and industry. In this paper, we demonstrate the application of a modular microfluidic system for execution of enzyme assays that allow determining the kinetic parameters of the enzymatic reactions such as Vmax–the maximum rate of reaction and KM–the Michaelis constant. For experiments, the fluorogenic carbonate as a probe for a rapid determination of the kinetic parameters of hydrolases, such as lipases and esterases, was used. The microfluidic system together with the method described yields the kinetic constants calculated from the concentration of enzymatic product changes via a Michaelis–Menten model using the Lambert function W(x). This modular microfluidic system was validated on three selected enzymes (hydrolases).
Jankowski, Pawel,Samborski, Adam,Ostaszewski, Ryszard,Garstecki, Piotr
p. 727 - 734
(2019/05/10)

Copper-Triggered Bioorthogonal Cleavage Reactions for Reversible Protein and Cell Surface Modifications
Temporal and reversible control over protein and cell conjugations holds great potential for traceless release of antibody-drug conjugates (ADCs) on tumor sites as well as on-demand altering or removal of targeting elements on cell surface. We herein developed a bioorthogonal and traceless releasable reaction on proteins and intact cells to fulfill such purposes. A systematic survey of transition metals in catalyzing the bioorthogonal cleavage reactions revealed that copper complexes such as Cu(I)-BTTAA and dual-substituted propargyl (dsPra) or propargyloxycarbonyl (dsProc) moieties offered a bioorthogonal releasable pair for reversible blockage and rescue of primary amines and phenol alcohols on small molecule drugs, protein side chains, as well as intact cell surface. For proof-of-concept, we employed such Cu(I)-BTTAA/dsProc and Cu(I)-BTTAA/dsPra pairs as a "traceless linker" strategy to construct cleavable ADCs to unleash cytotoxic compounds on cancer cells in situ and as a "reversible modification" strategy for cell surface engineering. Furthermore, by coupling with the genetic code expansion strategy, we site-specifically modulated ligand-receptor interactions on live cell membranes. Together, our work expanded the transition-metal-mediated bioorthogonal cleavage tool kit from terminal decaging to internal-linker breakage, which offered a temporal and reversible conjugation strategy on therapeutic proteins and cells.
Wang, Xin,Liu, Yanjun,Fan, Xinyuan,Wang, Jie,Ngai, William Shu Ching,Zhang, Heng,Li, Jiaofeng,Zhang, Gong,Lin, Jian,Chen, Peng R.
p. 17133 - 17141
(2019/11/03)

Mechanically Triggered Small Molecule Release from a Masked Furfuryl Carbonate
Stimuli-responsive polymers that release small molecules under mechanical stress are appealing targets for applications ranging from drug delivery to sensing. Here, we describe a modular mechanophore design platform for molecular release via a mechanically triggered cascade reaction. Mechanochemical activation of a furan-maleimide Diels-Alder adduct reveals a latent furfuryl carbonate that subsequently decomposes under mild conditions to release a covalently bound cargo molecule. The computationally guided design of a reactive secondary furfuryl carbonate enables the decomposition and release to proceed quickly at room temperature after unmasking via mechanical force. This general strategy is demonstrated using ultrasound-induced mechanical activation to release a fluorogenic coumarin payload from a polymer incorporating a chain-centered mechanophore.
Hu, Xiaoran,Zeng, Tian,Husic, Corey C.,Robb, Maxwell J.
supporting information
p. 15018 - 15023
(2019/11/02)

Novel C7-substituted coumarins as selective monoamine oxidase inhibitors: Discovery, synthesis and theoretical simulation
There is a continued need to develop new selective human monoamine oxidase (hMAO) inhibitors that could be beneficial for the treatment of neurological diseases. However, hMAOs are closely related with high sequence identity and structural similarity, which hinders the development of selective MAO inhibitors. “Three-Dimensional Biologically Relevant Spectrum (BRS-3D)” method developed by our group has demonstrated its effectiveness in subtype selectivity studies of receptor and enzyme ligands. Here, we report a series of novel C7-substituted coumarins, either synthesized or commercially purchased, which were identified as selective hMAO inhibitors. Most of the compounds demonstrated strong activities with IC50 values (half-inhibitory concentration) ranging from sub-micromolar to nanomolar. Compounds, FR1 and SP1, were identified as the most selective hMAO-A inhibitors, with IC50 values of 1.5 nM (selectivity index (SI) 50 of 18 nM and 15 nM (SI > 2.74 and SI > 2.82). Docking calculations and molecular dynamic simulations were performed to elucidate the selectivity preference and SAR profiles.
Wang, Dong,Hong, Ren-Yuan,Guo, Mengyao,Liu, Yi,Chen, Nianhang,Li, Xun,Kong, De-Xin
(2019/11/19)

Sulfonation of carbonized xylan-type hemicellulose: A renewable and effective biomass-based biocatalyst for the synthesis of O- and N-heterocycles
The application of biomass-based carbonaceous solid acids in catalysis is attracting increasing attention in the field of chemistry. In this study, a heterogeneous carbon-based solid acid biocatalyst (CXH-SO3H) with regular spherical structure was synthesized from xylan-type hemicellulose (XH) by a simple two-step method. The catalyst was successfully applied in the synthesis of O- and N-heterocycles with yields of 80-99% and 60-97%, respectively. In view of environment and economy, CXH-SO3H shows the merits of environmental friendliness, easy operation, simple work-up, excellent yields, and the avoidance of use of organic solvents and expensive catalysts. Moreover, the as-synthesized solid acid catalyst could be used for several cycles without significant loss in its catalytic activity. The results of FT-IR, XRD, and SEM showed that no distinct differences in physico-chemical structures of CXH-SO3H were observed. Thus, the eco-friendly CXH-SO3H catalyst is a promising candidate for green synthesis of O- and N-heterocycles from low-cost feed-stocks and has good prospect in partially substituting commercially available solid and liquid acid catalysts and precious metal catalysts.
Ma, Jiliang,Peng, Xinwen,Zhong, Linxin,Sun, Runcang
p. 9140 - 9150
(2018/06/11)

Synthesis method of coumarin compounds
The invention relates to a synthesis method of coumarin compounds. The method particularly comprises the following steps: performing reaction for 40 to 120 minutes by taking substituted phenol and beta-keto ester as substrates and DES as a catalyst under the condition of no solvents and at the temperature of 50 to 100 DEG C to prepare the coumarin compounds. In the preparation process of the coumarin compounds, other organic solvents do not need to be added and the DES serves as a reaction catalyst and solvent. The DES can be reused and is environment-friendly, and the catalytic effect basically maintains unchanged after the DES is recovered for four times. The preparation method provided by the invention is simple in process, high in catalytic activity and high in yield; and after reaction, treatment is simple, convenient and environment-friendly.
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Paragraph 0043; 0045; 0046; 0047; 0049

(2018/06/23)

Synthesis of Ethylene Tethered Isatin-Coumarin Hybrids and Evaluation of Their in vitro Antimycobacterial Activities
A series of novel isatin-coumarin derivatives tethered through ethylene were designed, synthesized, and evaluated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H37Rv and multidrug-resistant tuberculosis (MDR-TB). All hybrids exhibited potential antimycobacterial activities against MTB H37Rv and MDR-TB with minimum inhibitory concentration (MIC) ranging from 32 to 256?μg/mL. In particular, the hybrid 4h (MIC: 50 and 32?μg/mL) was most active against MTB H37Rv and MDR-TB strains, which was 2 and >4 folds more potent than the first-line antitubercular agents rifampicin (MIC: 64?μg/mL) and isoniazid (MIC: >128?μg/mL) against MDR-TB, warrant further optimization.
Gao, Tao,Zeng, Zhigang,Wang, Gangqiang,Sun, Shaofa,Liu, Yi
p. 1484 - 1488
(2018/04/26)

New enzymatic and mass spectrometric methodology for the selective investigation of gut microbiota-derived metabolites
Gut microbiota significantly impact human physiology through metabolic interaction. Selective investigation of the co-metabolism of bacteria and their human host is a challenging task and methods for their analysis are limited. One class of metabolites associated with this co-metabolism are O-sulfated compounds. Herein, we describe the development of a new enzymatic assay for the selective mass spectrometric investigation of this phase II modification class. Analysis of human urine and fecal samples resulted in the detection of 206 sulfated metabolites, which is three times more than reported in the Human Metabolome Database. We confirmed the chemical structure of 36 sulfated metabolites including unknown and commonly reported microbiota-derived sulfated metabolites using synthesized internal standards and mass spectrometric fragmentation experiments. Our findings demonstrate that enzymatic sample pre-treatment combined with state-of-the-art metabolomics analysis represents a new and efficient strategy for the discovery of unknown microbiota-derived metabolites in human samples. Our described approach can be adapted for the targeted investigation of other metabolite classes as well as the discovery of biomarkers for diseases affected by microbiota.
Ballet, Caroline,Correia, Mário S. P.,Conway, Louis P.,Locher, Theresa L.,Lehmann, Laura C.,Garg, Neeraj,Vujasinovic, Miroslav,Deindl, Sebastian,L?hr, J.-Matthias,Globisch, Daniel
p. 6233 - 6239
(2018/08/07)

Supramolecular Assemblies for Transporting Proteins Across an Immiscible Solvent Interface
Polymeric supramolecular assemblies that can effectively transport proteins across an incompatible solvent interface are described. We show that electrostatics and ligand-protein interactions can be used to selectively transport proteins from an aqueous phase to organic phase. These transported proteins have been shown to maintain their tertiary structure and function. This approach opens up new possibilities for application of supramolecular assemblies in sensing, diagnostics and catalysis.
Gao, Jingjing,Zhao, Bo,Wang, Meizhe,Serrano, Mahalia A. C.,Zhuang, Jiaming,Ray, Moumita,Rotello, Vincent M.,Vachet, Richard W.,Thayumanavan
supporting information
p. 2421 - 2425
(2018/02/28)

A new coumarin-carbonothioate-based turn-on fluorescent chemodosimeter for selective detection of Hg2+
A new fluorescent chemodosimeter 1 comprising coumarin as a fluorophore and a carbonothioate group as recognition unit was designed and synthesized. Its structure was confirmed by single crystal X-ray crystallography. The compound 1 shows almost no fluorescence in HEPES buffer (10 mM, pH 7.0), while displays obvious fluorescence enhancement after addition of Hg2+ over other metal ions. The recognition mechanism is attributed to the Hg2+-promoted hydrolysis reaction. In addition, 1 could be successfully applied to detect the concentrations of Hg2+ in real water samples by fluorescence turn-on response.
Li, Qiao,Hu, Yang,Hou, Hai-Nan,Yang, Wen-Nan,Hu, Sheng-Li
supporting information
p. 705 - 708
(2017/12/26)

Synthesis of new coumarin tethered isoxazolines as potential anticancer agents
A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b, 7c, 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC50 values of 8.8, 10.5, 9.2 and 4.5 μM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration. Further, we have chosen compound 7c to check its efficacy in Ehrlich Ascites Carcinoma animal model in-vivo for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature such as regression of tumor volume. The present study indicates the scope of developing into potent anticancer drug in near future.
Lingaraju, Gejjalagere S.,Balaji, Kyathegowdanadoddi S.,Jayarama, Shankar,Anil, Seegehalli M.,Kiran, Kuppalli R.,Sadashiva, Maralinganadoddi P.
supporting information
p. 3606 - 3612
(2018/11/06)

Fluorescent microplate assay method for high-throughput detection of lipase transesterification activity
This study describes a sensitive and fluorescent microplate assay method to detect lipase transesterification activity. Lipase-catalyzed transesterification between butyryl 4-methyl umbelliferone (Bu-4-Mu) and methanol in tert-butanol was selected as the model reaction. The release of 4-methylumbelliferone (4-Mu) in the reaction was determined by detecting the fluorescence intensity at λex 330 nm and λem 390 nm. Several lipases were used to investigate the accuracy and efficiency of the proposed method. Apparent Michaelis constant (Km) was calculated for transesterification between Bu-4-Mu and methanol by the lipases. The main advantages of the assay method include high sensitivity, inexpensive reagents, and simple detection process.
Zheng, Jianyong,Wei, Wei,Lan, Xing,Zhang, Yinjun,Wang, Zhao
p. 26 - 28
(2018/03/21)

Design of fluorogenic probes and fluorescent-tagged inhibitors for γ-glutamyl cyclotransferase
A tumor-related protein, human chromosome 7 ORF 24 (C7orf24), is involved in regulation of the glutathione homeostasis cycle as a γ-glutamyl cyclotransferase (GGCT). The singular substrate preference of this enzyme had long hampered its chemical probe development. That is, substrate of GGCT is definitely ‘γ-Glu-Xaa’, where Xaa is an L-α-amino acid. Based on the structure of substrates and GGCT fluorogenic probes, LISA-4/101, we succesfully developed a fluorescent-tagged inhibitor, gKFA. These chemical tools will assist cancer-related researches in the future.
Yoshiya, Taku,Ii, Hiromi,Tsuda, Shugo,Mochizuki, Masayoshi,Kageyama, Susumu,Yoshiki, Tatsuhiro
p. 618 - 623
(2017/08/15)

Synthesis of pyrazole-4-carbaldehyde derivatives for their antifungal activity
A series of pyrazole-4-carbaldehyde containing coumarin derivatives (9a–l) were achieved starting from substituted 6-hydroxy-4-methyl coumarins in a facial manner by Vilsmeier–Haack Formylation reaction in good yields, and their chemical structures were determined by Fourier transform infrared, 1H, 13C-nuclear magnetic resonance and mass spectroscopic techniques. Compounds 9a–l were docked into monoamine oxidase from Aspergillus niger and shown strong π-stacking interactions with the cage forming amino acids of Trp430 and Phe466, and were also further evaluated against antifungal activity on Aspergillus niger by taking Clotrimazole as standard. Out of twelve synthesized compounds 9a, 9b, 9g, and 9h were showed good and 9c, 9d, 9e, 9i, 9j, and 9k were showed moderate antifungal activity.
Reddy, Vadiyala Naveen,Yamini, Lingala,Rao, Yerrabelly Jayaprakash,Rao, Chitneni Prasad
p. 1664 - 1674
(2017/06/27)

Fluorescent Neuraminidase Assay Based on Supramolecular Dye Capture after Enzymatic Cleavage
A conceptually new type of enzymatic cleavage assay is reported that utilizes in situ supramolecular capture of the fluorescent product. A squaraine-derived substrate with large blocking groups at each end of its structure cannot be threaded by a tetralactam macrocycle until the blocking groups are removed by enzyme cleavage. A prototype design responds to viral neuraminidase, an indicator of influenza infection, and also measures susceptibility of the sample to neuraminidase inhibitor drugs. The substrate structure incorporates three key features: (a) a bis(4-amino-3-hydroxyphenyl)squaraine core with bright deep-red fluorescence and excellent photostability, (b) an N-methyl group at each end of the squaraine core that ensures fast macrocycle threading kinetics, and (c) sialic acid blocking groups that prevent macrocycle threading until they are removed by viral neuraminidase. The enzyme assay can be conducted in aqueous solution where dramatic colorimetric and fluorescence changes are easily observed by the naked eye. Alternatively, affinity capture beads coated with macrocycle can be used to immobilize the liberated squaraine and enable a range of heterogeneous analysis options. With further optimization, this new type of neuraminidase assay may be useful in a point of care clinic to rapidly diagnose influenza infection and also determine which of the approved antiviral inhibitor drugs is likely to be the most effective treatment for an individual patient. The assay design is generalizable and can be readily modified to monitor virtually any type of enzyme-catalyzed cleavage reaction.
Liu, Wenqi,Gómez-Durán, César F. A.,Smith, Bradley D.
supporting information
p. 6390 - 6395
(2017/09/12)

Anti-influenza activity of monoterpene-containing substituted coumarins
Compounds simultaneously carrying the monoterpene and coumarin moieties have been tested for cytotoxicity and inhibition of activity against influenza virus A/California/07/09 (H1N1)pdm09. The structure of substituents in the coumarin framework, as well as the structure and the absolute configuration of the monoterpenoid moiety, are shown to significantly influence the anti-influenza activity and cytotoxicity of the compounds under study. The compounds with a bicyclic pinane framework exhibit the highest selectivity indices (the ratios between the cytotoxicity and the active dose). The derivative of (?)-myrtenol 15c, which is characterized by promising activity, low cytotoxicity, and synthetic accessibility, has the greatest potential among this group of compounds. It exhibited the highest activity when added to the infected cell culture at early stages of viral reproduction.
Khomenko, Tatyana M.,Zarubaev, Vladimir V.,Orshanskaya, Iana R.,Kadyrova, Renata A.,Sannikova, Victoria A.,Korchagina, Dina V.,Volcho, Konstantin P.,Salakhutdinov, Nariman F.
supporting information
p. 2920 - 2925
(2017/06/01)

Design, synthesis and biological evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of Alzheimer's disease
Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and Aβ (1–42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 μM for eeAChE; 2.32 μM for eqBuChE; 1.57 μM for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit Aβ (1–42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit.
Lan, Jin-Shuai,Ding, Yue,Liu, Yun,Kang, Ping,Hou, Jian-Wei,Zhang, Xin-Yu,Xie, Sai-Sai,Zhang, Tong
p. 48 - 59
(2017/08/10)

A fluorescent coumarin-based probe for the fast detection of cysteine with live cell application
A new coumarin-based fluorescent probe, containing an allylic esters group, has been designed and synthesized for sensing cysteine in physiological pH. In this fluorescent probe, the coumarin was applied as the fluorophore and an allylic esters group was combined as both a fluorescence quencher and a recognition unit. The probe can selectively and sensitively detect cysteine (Cys) over homocysteine, glutathione, and other amino acids, and has a rapid response time of 30 min and a low detection limit of 47.7 nM. In addition, the probe could be applied for cell imaging with low cytotoxicity.
Zeng, Rui-Feng,Lan, Jin-Shuai,Li, Xiao-Die,Liang, Hui-Fen,Liao, Yan,Lu, Ying-Jie,Zhang, Tong,Ding, Yue
(2017/10/13)

High yield preparation of ganglioside GM1 using recombinant sialidase from Cellulosimicrobium cellulans
Cellulosimicrobium cellulans employs extracellular sialidase to selectively convert polysialogangliosides to ganglioside GM1. We cloned this novel sialidase gene (ccsia) from C. cellulans sp. 21, and overexpressed recombinant sialidase (CcSia) protein in E. coli BL21 (DE3) by high cell density fermentation. The presence of an N-terminal hexa-His tag allowed for purification using nickel affinity chromatography (2.3-fold, specific activity 41.5?U/mg). As determined by gel electrophoresis and gel filtration chromatography, the molecular weight of CcSia was found to be about 75?kDa, consistent with sequence analysis (75,271?Da). CcSia transformed polysialogangliosides GD1a, GD1b and GT1b into GM1. For this reaction, the response surface approach showed that optimal conditions in a 1-L system were 2?h incubation at 32.5?°C and pH 5.2, with substrate concentrations of 10?g/L and crude enzyme concentration 1?g/L, respectively. Under above conditions, 10?g/L of ganglioside was completely converted to the product GM1 with a yield of 52%. Our studies demonstrate CcSia could be used for industrial preparation of ganglioside GM1 by the pharmaceutical industry.
Yuan, Ye,Ji, Li,Hu, Yanbo,Hu, Chenxing,Chen, Honglei,Gao, Juan,Zhou, Yifa
p. 92 - 97
(2017/06/21)

Process for preparing particles which have a hydrophilic core coated with a hydrophobic polymeric layer
This method of preparing particles having a hydrophilic core coated with a hydrophilic core coated with a hydrophobic polymeric layer includes the steps of: preparing an aqueous phase comprising at least one hydrophilic optical brightener or colorant; preparing an organic phase including at least one hydrophobic polymer; forming a water-in-oil inverse emulsion by adding the aqueous phase into the organic phase; forming the particles by thermal quenching of the emulsion; and isolating the particles thus obtained.
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(2016/06/01)