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Publications (10 of 22) Show all publications
Kathiravan, S. & Nicholls, I. A. (2017). Cobalt Catalyzed, Regioselective C(sp(2))-H Activation of Amides with 1,3-Diynes. Organic Letters, 19(18), 4758-4761
Open this publication in new window or tab >>Cobalt Catalyzed, Regioselective C(sp(2))-H Activation of Amides with 1,3-Diynes
2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 18, p. 4758-4761Article in journal (Refereed) Published
Abstract [en]

The development of a first row transition metal (cobalt)-based catalyst for the as yet unexplored CH activation-driven reaction of 1,3-diynes, themselves a functional class of interest in a range of application areas, to form isoquinolinonesan important structural motif in a number of biologically active substancesis presented. This versatile and inexpensive catalyst employs a covalently attached bidendate-directing group, 8-aminoquinoline. The template directs the CH activation and facilitates the synthesis of a wide range of alkynylated heterocycles under mild conditions and with excellent regioselectivity. This strategy provides a novel and efficient route to diverse heterocyclic frameworks as demonstrated by its late stage application in bisheterocycle syntheses.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-336482 (URN)10.1021/acs.orglett.7b02119 (DOI)000411304300014 ()28846427 (PubMedID)
Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2017-12-15Bibliographically approved
Suriyanarayanan, S., Mandal, S., Ramanujam, K. & Nicholls, I. (2017). Electrochemically synthesized molecularly imprinted polythiophene nanostructures as recognition elements for an aspirin-chemosensor. Sensors and actuators. B, Chemical, 253, 428-436
Open this publication in new window or tab >>Electrochemically synthesized molecularly imprinted polythiophene nanostructures as recognition elements for an aspirin-chemosensor
2017 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 253, p. 428-436Article in journal (Refereed) Published
Abstract [en]

A chemosensor utilizing electro-polymerized film, as recognition element, has been devised and tested for selective determination of aspirin. The sensor consists of molecularly imprinted polymer (MIP) recognition elements electrodeposited as polymeric nanowires on gold-coated quartz resonator. A nano structures were prepared by electrochemical co-polymerization of the preformed complex between the template, aspirin, the functional monomers, 3-thienylboronic acid (3-TBA) and 3-thiopheneacetic acid (3-TAA), and thiophene, which was employed as a cross-linker. This nanostructure upon leaching aspirin serve as MIP. Polymerizations were performed in acetonitrile (MIP-org) as well as a micelle forming medium (MIP-mic). For MIP nanowire (MIP-ano) synthesis, sacrificial alumina templates were used during electro-polymerization in acetonitrile. Scanning electron microscope studies revealed compactly arranged polythiophene nanowires of uniform thickness in MIP-ano film, and MIP-mic film produced aggregated micron sized polymer structures. Density functional theoretical studies indicated a stable hydrogen bond-based complexation of aspirin by 3-TBA and 3-TAA in the pre-polymerization mixture implying that the MIP film thus prepared could selectively rebind the aspirin template. The MIP-ano-based chemosensor was sensitive towards aspirin (0.5-10 mM), over clinically relevant range (0.15-0.5 mM) under optimized FIA conditions. The sensitivity (20.62 Hz/mM) of the MIP-ano was eight and fifteen times higher than the MIP-mic (2.80 Hz/mM) and MIP-org (1.10 Hz/mM). Notably, the sensor selectively discriminates aspirin from structurally or functionally related interferants and metabolites, such as, salicylic acid, acetylsalicyloyl chloride and ibuprofen.

Keywords
Electrochemical polymerization, Aspirin chemosensor, Quartz crystal microbalance, Sacrificial template
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-339731 (URN)10.1016/j.snb.2017.05.076 (DOI)000411124800051 ()
Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-01-26Bibliographically approved
Kathiravan, S. & Nicholls, I. A. (2017). Monoprotected L-Amino Acid (L-MPAA), Accelerated Bromination, Chlorination, and Iodination of C(sp²)-H Bonds by Iridium(III) Catalysis. Chemistry - A European Journal, 23(29), 7031-7036
Open this publication in new window or tab >>Monoprotected L-Amino Acid (L-MPAA), Accelerated Bromination, Chlorination, and Iodination of C(sp²)-H Bonds by Iridium(III) Catalysis
2017 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 29, p. 7031-7036Article in journal (Refereed) Published
Abstract [en]

Halogenated arenes are important structural motifs commonly found in biologically active molecules and used for a variety of transformations in organic synthesis. Herein, we report the mono-protected L-amino acid (L-MPAA) accelerated iridium(III)-catalyzed halogenation of (hetero)anilides at room temperature. This reaction constitutes the first example of an iridium(III)/L-MPAA-catalyzed general halogenation of (hetero)arenes through C(sp²)-H activation. Furthermore, we demonstrate the potential utility of our method through its use in the synthesis of a quinolone derivative.

Keywords
anilides, C-H activation, halogenation, iridium, L-MPAA
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-325695 (URN)10.1002/chem.201700280 (DOI)000401992100016 ()28221698 (PubMedID)
Funder
Swedish Research Council, 2014-4573
Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2017-06-27Bibliographically approved
Kathiravan, S. & Nicholls, I. A. (2017). Rhodium(III)-catalysed, redox-neutral C(sp(2))-H alkenylation using pivalimide as a directing group with internal alkynes. Tetrahedron Letters, 58(1), 1-4
Open this publication in new window or tab >>Rhodium(III)-catalysed, redox-neutral C(sp(2))-H alkenylation using pivalimide as a directing group with internal alkynes
2017 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 58, no 1, p. 1-4Article in journal (Refereed) Published
Abstract [en]

In the presence of [RhCp*Cl(2)l(2), N-pivaloyl anilines react with internal alkynes to give the corresponding 2-alkenylpivalimides under redox neutral conditions through C-H activation. This redox neutral hydroarylation, which does not require an external organic acid, unlocks a regioselective synthetic route to 2-alkenyl anilines and is generally applicable to diversely substituted electron rich and electron poor pivalimides.

Keywords
Hydroarylation, Internal alkynes, Redox-neutral, Rhodium catalysis, Pivalimide
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-316041 (URN)10.1016/j.tetlet.2016.11.039 (DOI)000392038800001 ()000392038800001 (PubMedID)
Funder
Swedish Research Council, 2014-4573The Kempe Foundations, 2010-0223
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2017-11-29Bibliographically approved
Golker, K., Olsson, G. D. & Nicholls, I. (2017). The influence of a methyl substituent on molecularly imprinted polymer morphology and recognition - Acrylic acid versus methacrylic acid. European Polymer Journal, 92, 137-149
Open this publication in new window or tab >>The influence of a methyl substituent on molecularly imprinted polymer morphology and recognition - Acrylic acid versus methacrylic acid
2017 (English)In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 92, p. 137-149Article in journal (Refereed) Published
Abstract [en]

In this report, we have investigated factors contributing to the morphology and template recognition of bupivacaine-imprinted copolymers of methacrylic acid (MAA) and ethyleneglycol dimethacrylate (EGDMA). To this end, MAA, the most commonly used functional monomer in non-covalent molecular imprinting protocols, was compared and contrasted with the closely related acrylic acid (AA) in terms of polymer morphologies, recognition characteristics, and molecular level events in the corresponding pre-polymerization mixtures. Two series of analogous bupivacaine-imprinted EGDMA-copolymers containing increasing fractions of either AA or MAA were studied through all-component MD simulations in the pre-polymerization phase, equilibrium binding experiments on corresponding synthesized polymers and morphology characterization by N-2-sorption measurements. A higher degree of hydrogen bonding frequency between respective functional monomer and bupivacaine was recorded for the mixtures containing AA compared to those containing MAA. In contrast, results from binding experiments demonstrated higher binding capacities for the polymers prepared with MAA than for those prepared with AA, which is explained by differences in polymer morphology. The surface areas and pore volumes of the AA-polymers were higher than for the MAA-polymers and the overall pore structure in the AA-polymers was ink-bottle shaped while the pores in the MAA-polymers were slit-shaped. We suggest that the methyl substituent of MAA contributes to differences in the reaction kinetics for AA and MAA during polymerization and resulted in different morphologies, in particular pore shape, which affected mass-transfer and consequently the binding qualities of the materials.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD, 2017
Keywords
Molecularly imprinted polymer, Molecular dynamics, Molecular recognition, Morphology, Methacrylic acid, Acrylic acid
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-328971 (URN)10.1016/j.eurpolymj.2017.04.043 (DOI)000404315600013 ()
Funder
Swedish Research Council, 2014-4573EU, FP7, Seventh Framework Programme, 602699
Available from: 2017-09-12 Created: 2017-09-12 Last updated: 2017-09-12Bibliographically approved
Chavan, S., Abdelaziz, A., Wiklander, J. G. & Nicholls, I. A. (2016). A k-nearest neighbor classification of hERG K+ channel blockers. Journal of Computer-Aided Molecular Design, 30(3), 229-236
Open this publication in new window or tab >>A k-nearest neighbor classification of hERG K+ channel blockers
2016 (English)In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 30, no 3, p. 229-236Article in journal (Refereed) Published
Abstract [en]

A series of 172 molecular structures that block the hERG K+ channel were used to develop a classification model where, initially, eight types of PaDEL fingerprints were used for k-nearest neighbor model development. A consensus model constructed using Extended-CDK, PubChem and Substructure count fingerprint-based models was found to be a robust predictor of hERG activity. This consensus model demonstrated sensitivity and specificity values of 0.78 and 0.61 for the internal dataset compounds and 0.63 and 0.54 for the external (PubChem) dataset compounds, respectively. This model has identified the highest number of true positives (i.e. 140) from the PubChem dataset so far, as compared to other published models, and can potentially serve as a basis for the prediction of hERG active compounds. Validating this model against FDA-withdrawn substances indicated that it may even be useful for differentiating between mechanisms underlying QT prolongation.

Keywords
Classification model, hERG blockers, Ikr, KCNH2, k-nearest neighbor (k-NN), Toxicity
National Category
Chemical Sciences Computer and Information Sciences
Identifiers
urn:nbn:se:uu:diva-294332 (URN)10.1007/s10822-016-9898-z (DOI)000373117200004 ()26860111 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 238701
Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2018-01-10Bibliographically approved
Shoravi, S., Olsson, G. D., Karlsson, B. C. G., Bexborn, F., Abghoui, Y., Hussain, J., . . . Nicholls, I. A. (2016). In silico screening of molecular imprinting prepolymerization systems: oseltamivir selective polymers through full-system molecular dynamics-based studies. Organic and biomolecular chemistry, 14(18), 4210-4219
Open this publication in new window or tab >>In silico screening of molecular imprinting prepolymerization systems: oseltamivir selective polymers through full-system molecular dynamics-based studies
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2016 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 18, p. 4210-4219Article in journal (Refereed) Published
Abstract [en]

All-component molecular dynamics studies were used to probe a library of oseltamivir molecularly imprinted polymer prepolymerization mixtures. Polymers included one of five functional monomers (acrylamide, hydroxyethylmethacrylate, methacrylic acid, 2-(triflouromethyl)acrylic acid, 4-vinylpyridine) and one of three porogens (acetonitrile, chloroform, methanol) combined with the crosslinking agent ethylene glycol dimethacrylate and initiator 2,2'-azobis(2-methylpropionitrile). Polymers were characterized by nitrogen gas sorption measurements and SEM, and affinity studies performed using radioligand binding in various media. In agreement with the predictions made from the simulations, polymers prepared in acetonitrile using either methacrylic or trifluoromethacrylic acid demonstrated the highest affinities for oseltamivir. Further, the ensemble of interactions observed in the methanol system provided an explanation for the morphology of polymers prepared in this solvent. The materials developed here offer potential for use in solid-phase extraction or for catalysis. The results illustrate the strength of this in silico strategy as a potential prognostic tool in molecularly imprinted polymer design.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-298032 (URN)10.1039/c6ob00305b (DOI)000375610600007 ()27043914 (PubMedID)
Funder
Swedish Research Council, 2006-6041, 2014-4573
Available from: 2016-07-11 Created: 2016-06-29 Last updated: 2017-11-28Bibliographically approved
Huang, S., Engberg, A. E., Jonsson, N., Sandholm, K., Nicholls, I. A., Mollnes, T. E., . . . Ekdahl, K. N. (2016). Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood. Biomaterials, 77, 111-119
Open this publication in new window or tab >>Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood
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2016 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 77, p. 111-119Article in journal (Refereed) Published
Abstract [en]

Background: Inappropriate and uncontrolled activation of the cascade systems in the blood is a driving force in adverse inflammatory and thrombotic reactions elicited by biomaterials, but limited data are available on the activation of the contact system by polymers and the present study was undertaken to investigate these mechanisms in established models. Methods: Polymer particles were incubated in (1) EDTA-plasma (10 mM) to monitor the adsorption of 20 selected proteins; (2) lepirudin-anticoagulated plasma to evaluate contact system activation, monitored by the formation of complexes between the generated proteases factor[F]XIIa, FXIa and kallikrein and the serpins C1-inhibitor [C1INH] and antithrombin [AT]; (3) lepirudin-anticoagulated whole blood to determine cytokine release. Results: Strong negative correlations were found between 10 cytokines and the ratio of deposited FXII/C1INH, generated FXIIa-C1INH complexes, and kallikrein-C1INH complexes. Formation of FXIIa-C1INH complexes correlated negatively with the amount of C3a and positively with deposited IgG. Conclusions: A reciprocal relationship was found between activation of the contact system and the complement system induced by the polymers studied here. The ratios of FXII/C1INH or C4/C4BP, adsorbed from EDTA-plasma are useful surrogate markers for cytokine release and inflammatory response to materials intended for blood contact.

Keywords
Biomaterials, Complement system, Contact system, FXII, In vitro screening
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-274422 (URN)10.1016/j.biomaterials.2015.10.067 (DOI)000367118200010 ()
Funder
Swedish Research CouncilEU, European Research Council, 602699Carl Tryggers foundation
Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2017-11-30Bibliographically approved
Golker, K. & Nicholls, I. A. (2016). The effect of crosslinking density on molecularly imprinted polymer morphology and recognition. European Polymer Journal, 75, 423-430
Open this publication in new window or tab >>The effect of crosslinking density on molecularly imprinted polymer morphology and recognition
2016 (English)In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 75, p. 423-430Article in journal (Refereed) Published
Abstract [en]

In this report, the crosslinking density of bupivacaine molecularly imprinted methacrylic acid (MAA)-ethylene glycol dimethacrylate (EGDMA) copolymers was investigated through replacement of EGDMA by methyl methacrylate (MMA). The effects were examined using a series of full-scale MD simulations of pre-polymerization mixtures, equilibrium rebinding studies on the corresponding synthesized polymers and morphology characterization through nitrogen sorption measurements. While the extent of hydrogen bonding between the functional monomer MAA and bupivacaine observed in the MD pre-polymerization mixtures was comparable in each of the systems studied, the decrease in degree of crosslinking impacted directly on polymer morphology as observed in BET and BJH studies of surface area and porosity. Further, decreases in the crosslinking density induced reductions in template rebinding capacity as seen from a series of radio-ligand binding studies, demonstrating the importance of crosslinking on the performance of molecularly imprinted MAA-EGDMA copolymers, the polymer system most commonly used in molecular imprinting science and technology.

Keywords
Molecularly imprinted polymer, Molecular dynamics, Molecular recognition, Molecular imprinting, Morphology, Crosslinking
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-281840 (URN)10.1016/j.eurpolymj.2016.01.008 (DOI)000370309400036 ()
Funder
Swedish Research Council, 2014-4573EU, FP7, Seventh Framework Programme, 602699
Available from: 2016-04-06 Created: 2016-03-30 Last updated: 2017-11-30Bibliographically approved
Chavan, S., Friedman, R. & Nicholls, I. A. (2015). Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy. International Journal of Molecular Sciences, 16(5), 11659-11677
Open this publication in new window or tab >>Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy
2015 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, no 5, p. 11659-11677Article in journal (Refereed) Published
Abstract [en]

A k-nearest neighbor (k-NN) classification model was constructed for 118 RDT NEDO (Repeated Dose Toxicity New Energy and industrial technology Development Organization; currently known as the Hazard Evaluation Support System (HESS)) database chemicals, employing two acute toxicity (LD50)-based classes as a response and using a series of eight PaDEL software-derived fingerprints as predictor variables. A model developed using Estate type fingerprints correctly predicted the LD50 classes for 70 of 94 training set chemicals and 19 of 24 test set chemicals. An individual category was formed for each of the chemicals by extracting its corresponding k-analogs that were identified by k-NN classification. These categories were used to perform the read-across study for prediction of the chronic toxicity, i.e., Lowest Observed Effect Levels (LOEL). We have successfully predicted the LOELs of 54 of 70 training set chemicals (77%) and 14 of 19 test set chemicals (74%) to within an order of magnitude from their experimental LOEL values. Given the success thus far, we conclude that if the k-NN model predicts LD50 classes correctly for a certain chemical, then the k-analogs of such a chemical can be successfully used for data gap filling for the LOEL. This model should support the in silico prediction of repeated dose toxicity.

Keywords
k-nearest neighbor, classification model, Estate fingerprint, LD50, LOEL, read-across, category formation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-258545 (URN)10.3390/ijms160511659 (DOI)000356241400146 ()26006240 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 238701
Available from: 2015-07-15 Created: 2015-07-15 Last updated: 2017-12-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0407-6542

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