Publications by authors named "Alexandros Kiriazis"

16 Publications

  • Page 1 of 1

Treating cuff tear arthropathy by reverse total shoulder arthroplasty: do the inclination of the humeral component and the lateral offset of the glenosphere influence the clinical and the radiological outcome?

Eur J Orthop Surg Traumatol 2021 Apr 20. Epub 2021 Apr 20.

Orthopedic Practice Clinic (OPPK), Schuerbusch 55, 48143, Münster, Germany.

Purpose: Reverse total shoulder arthroplasty is widely used for the treatment of cuff tear arthropathy. Standard implants consist of a humeral component with an inclination angle of 155° and a glenosphere without lateral offset. Recently, lower inclination angles of the humeral component as well as lateralized glenospheres are implanted to provide better rotation of the arm and to decrease the rate of scapular notching. This study investigates the clinical and radiological results of a standard reverse total shoulder in comparison with an implant with an inclination angle of 135° in combination with a 4 mm lateralized glenosphere in context of cuff tear arthropathy.

Material And Methods: For this retrospective comparative analysis 42 patients treated by reverse total shoulder arthroplasty for cuff tear arthropathy were included. Twenty-one patients (m = 11, f = 10; mean age 76 years; mean follow-up 42 months) were treated with a standard 155° humeral component and a standard glenosphere with caudal eccentricity (group A), while twenty-one patients (m = 5, f = 16; mean age 72 years; mean follow-up 34 months) were treated with a 135° humeral component and 4 mm lateral offset of the glenosphere (group B). At follow-up patients of both groups were assessed with plain X-rays (a.p. and axial view), Constant Score, adjusted Constant Score, the subjective shoulder value and the range of motion.

Results: The clinical results were similar in both groups concerning the Constant Score (group A = 56.3 vs. group B = 56.1; p = 0.733), the adjusted CS (group A = 70.4% vs. group B = 68.3%; p = 0.589) and the SSV (group A = 72.0% vs. group B = 75.2%; p = 0.947). The range of motion of the operated shoulders did not differ significantly between group A and group B: Abduction = 98° versus 97.9°, p = 0.655; external rotation with the arm at side = 17.9° versus 18.7°, p = 0.703; external rotation with the arm positioned in 90° of abduction = 22.3° versus 24.7°, p = 0.524; forward flexion = 116.1° versus 116.7°, p = 0.760. The rate of scapular notching was higher (p = 0.013) in group A (overall: 66%, grade 1: 29%, grade 2: 29%, grade 3: 10%, grade 4: 0%) in comparison to group B (overall: 33%, grade 1: 33%, grade 2: 0%, grade 3: 0%, grade 4: 0%). Radiolucency around the humeral component was detected in two patients of group B. Stress shielding at the proximal humerus was observed in six patients of Group A (29%; cortical thinning and osteopenia in zone M1 and L1) and two patients of group B (10%; cortical thinning and osteopenia in zone M1 and L1). Calcifications of the triceps origin were observed in both groups (group A = 48% vs. group B = 38%).

Conclusion: Theoretically, a lower inclination angle of the humeral component and an increased lateral offset of the glenosphere lead to improved impingement-free range of motion and a decreased rate of scapular notching, when compared to a standard reverse total shoulder implant. This study compared two different designs of numerous options concerning the humeral component and the glenosphere. In comparison to a standard-fashioned implant with a humeral inclination of 155° and a standard glenosphere, implants with a humeral inclination angle of 135° and a 4 mm lateralized glenosphere lead to comparable clinical results and rotatory function, while the rate of scapular notching is decreased by almost 50%. While the different implant designs did not affect the clinical outcome, our results indicate that a combination of a lower inclination angle of the humeral component and lateralized glenosphere should be favored to reduce scapular notching.

Level Of Evidence: Level III, retrospective comparative study.
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http://dx.doi.org/10.1007/s00590-021-02976-4DOI Listing
April 2021

Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling.

Cancers (Basel) 2021 Feb 23;13(4). Epub 2021 Feb 23.

Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.

The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM-44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases.
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http://dx.doi.org/10.3390/cancers13040927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927014PMC
February 2021

Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment.

ACS Med Chem Lett 2020 Apr 17;11(4):605-610. Epub 2020 Feb 17.

Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), FI-00014 Helsinki, Finland.

Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in . malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of small mPPase inhibitors with 6-10 μM IC values in the test system. Promisingly, the compounds retained activity against mPPase in membranes and inhibited parasite growth.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153278PMC
April 2020

Screening for Thermotoga maritima Membrane-Bound Pyrophosphatase Inhibitors.

J Vis Exp 2019 11 23(153). Epub 2019 Nov 23.

Research Program in Molecular and Integrative Biosciences, University of Helsinki; School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds;

Membrane-bound pyrophosphatases (mPPases) are dimeric enzymes that occur in bacteria, archaea, plants, and protist parasites. These proteins cleave pyrophosphate into two orthophosphate molecules, which is coupled with proton and/or sodium ion pumping across the membrane. Since no homologous proteins occur in animals and humans, mPPases are good candidates in the design of potential drug targets. Here we present a detailed protocol to screen for mPPase inhibitors utilizing the molybdenum blue reaction in a 96 well plate system. We use mPPase from the thermophilic bacterium Thermotoga maritima (TmPPase) as a model enzyme. This protocol is simple and inexpensive, producing a consistent and robust result. It takes only about one hour to complete the activity assay protocol from the start of the assay until the absorbance measurement. Since the blue color produced in this assay is stable for a long period of time, subsequent assay(s) can be performed immediately after the previous batch, and the absorbance can be measured later for all batches at once. The drawback of this protocol is that it is done manually and thus can be exhausting as well as require good skills of pipetting and time keeping. Furthermore, the arsenite-citrate solution used in this assay contains sodium arsenite, which is toxic and should be handled with necessary precautions.
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http://dx.doi.org/10.3791/60619DOI Listing
November 2019

Mechanism of the Oxidation of Heptafulvenes to Tropones Studied by Online Mass Spectrometry and Density Functional Theory Calculations.

J Org Chem 2019 Nov 21;84(21):13975-13982. Epub 2019 Oct 21.

Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5 E) , FI-00014 University of Helsinki , Helsinki , Finland.

We have identified the most likely reaction mechanism for oxidizing heptafulvenes to the corresponding tropones by experimental and theoretical investigations. The experimental studies were done by coupling a three-dimensional printed miniaturized reactor with an integrated electrospray ionization needle to a mass spectrometer. Using the experimentally observed ions as a basis, nine alternative reaction pathways were investigated with density functional theory calculations. The lowest energy reaction pathway starts with the formation of an epoxide that is opened upon the addition of a second equivalent of the oxidizing species -chloroperoxybenzoic acid. The adduct formed then undergoes a Criegee-like rearrangement to yield a positively charged hemiketal, which on deprotonation dissociates into acetone and tropone. Overall, the reaction mechanism resembles a Hock-like rearrangement.
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http://dx.doi.org/10.1021/acs.joc.9b02078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076690PMC
November 2019

Asymmetry in catalysis by membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor.

Sci Adv 2019 05 22;5(5):eaav7574. Epub 2019 May 22.

Research Program in Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.

Membrane-bound pyrophosphatases are homodimeric integral membrane proteins that hydrolyze pyrophosphate into orthophosphates, coupled to the active transport of protons or sodium ions across membranes. They are important in the life cycle of bacteria, archaea, plants, and parasitic protists, but no homologous proteins exist in vertebrates, making them a promising drug target. Here, we report the first nonphosphorus allosteric inhibitor of the thermophilic bacterium membrane-bound pyrophosphatase and its bound structure together with the substrate analog imidodiphosphate. The unit cell contains two protein homodimers, each binding a single inhibitor dimer near the exit channel, creating a hydrophobic clamp that inhibits the movement of β-strand 1-2 during pumping, and thus prevents the hydrophobic gate from opening. This asymmetry of inhibitor binding with respect to each homodimer provides the first clear structural demonstration of asymmetry in the catalytic cycle of membrane-bound pyrophosphatases.
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http://dx.doi.org/10.1126/sciadv.aav7574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530997PMC
May 2019

Preparation and Characterization of Dentin Phosphophoryn-Derived Peptide-Functionalized Lignin Nanoparticles for Enhanced Cellular Uptake.

Small 2019 06 6;15(24):e1901427. Epub 2019 May 6.

Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Helsinki, Finland.

The surface modification of nanoparticles (NPs) using different ligands is a common strategy to increase NP-cell interactions. Here, dentin phosphophoryn-derived peptide (DSS) lignin nanoparticles (LNPs) are prepared and characterized, the cellular internalization of the DSS-functionalized LNPs (LNPs-DSS) into three different cancer cell lines is evaluated, and their efficacy with the widely used iRGD peptide is compared. It is shown that controlled extent of carboxylation of lignin improves the stability at physiological conditions of LNPs formed upon solvent exchange. Functionalization with DSS and iRGD peptides maintains the spherical morphology and moderate polydispersity of LNPs. The LNPs exhibit good cytocompatibility when cultured with PC3-MM2, MDA-MB-231, and A549 in the conventional 2D model and in the 3D cell spheroid morphology. Importantly, the 3D cell models reveal augmented internalization of peptide-functionalized LNPs and improve antiproliferative effects when the LNPs are loaded with a cytotoxic compound. Overall, LNPs-DSS show equal or even superior cellular internalization than the LNPs-iRGD, suggesting that DSS can also be used to enhance the cellular uptake of NPs into different types of cells, and release different cargos intracellularly.
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http://dx.doi.org/10.1002/smll.201901427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042775PMC
June 2019

Functionalization of carboxylated lignin nanoparticles for targeted and pH-responsive delivery of anticancer drugs.

Nanomedicine (Lond) 2017 Nov 29;12(21):2581-2596. Epub 2017 Sep 29.

Drug Research Program, Division of Pharmaceutical Chemistry & Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.

Aim: To carboxylate kraft lignin toward the functionalization of carboxylated lignin nanoparticles (CLNPs) with a block copolymer made of PEG, poly(histidine) and a cell-penetrating peptide and then evaluate the chemotherapeutic potential of the innovative nanoparticles.

Materials & Methods: The produced nanoparticles were characterized and evaluated in vitro for stability and biocompatibility and the drug release profiles and antiproliferative effect were also assessed.

Results: The prepared CLNPs showed spherical shape and good size distribution, good stability in physiological media and low cytotoxicity in all the tested cell lines. A poorly water-soluble cytotoxic agent was successfully loaded into the CLNPs, improving its release profiles in a pH-sensitive manner and showing an enhanced antiproliferative effect in the different cancer cells compared with a normal endothelial cell line.

Conclusion: The resulting CLNPs are promising candidates for anticancer therapy.
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http://dx.doi.org/10.2217/nnm-2017-0219DOI Listing
November 2017

Nucleophilic Substitution of Hydrogen Facilitated by Quinone Methide Moieties in Benzo[cd]azulen-3-ones.

Org Lett 2017 04 5;19(8):2030-2033. Epub 2017 Apr 5.

Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , P.O. Box 56, Viikinkaari 5 E, FI-00014 Helsinki, Finland.

The built-in o- and p-QM (QM = quinone methide) moieties in benzo[cd]azulen-3-ones account for an easy switch between the bridged 10π- and 6π-aromatic systems in organic synthesis. We report conjugate additions, oxidative nucleophilic substitutions of hydrogen, and reversible Michael additions under very mild conditions. In the presence of thiol nucleophiles, the protonated σ-adducts could be isolated and characterized. The typical preference for either the o- or p-QM moiety led to high regioselectivity. Furthermore, the inhibitory potency of the novel benzo[cd]azulenes against the human Pim-1 kinase was evaluated.
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http://dx.doi.org/10.1021/acs.orglett.7b00588DOI Listing
April 2017

In vitro evaluation of biodegradable lignin-based nanoparticles for drug delivery and enhanced antiproliferation effect in cancer cells.

Biomaterials 2017 03 2;121:97-108. Epub 2017 Jan 2.

Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014, Helsinki, Finland. Electronic address:

Currently, nanosystems have been developed and applied as promising vehicles for different biomedical applications. We have developed three lignin nanoparticles (LNPs): pure lignin nanoparticles (pLNPs), iron(III)-complexed lignin nanoparticles (Fe-LNPs), and FeO-infused lignin nanoparticles (FeO-LNPs) with round shape, narrow size distribution, reduced polydispersity and good stability at pH 7.4. The LNPs showed low cytotoxicity in all the tested cell lines and hemolytic rates below 12% after 12 h of incubation. Additionally, they induced hydrogen peroxide production in a small extent and time-dependent manner, and the interaction with the cells increased over time, exhibiting a dose-dependent cell uptake. Concerning the drug loading, pLNPs showed the capacity to efficiently load poorly water-soluble drugs and other cytotoxic agents, e.g. sorafenib and benzazulene (BZL), and improve their release profiles at pH 5.5 and 7.4 in a sustained manner. Furthermore, the BZL-pLNPs presented an enhanced antiproliferation effect in different cells compared to the pure BZL and showed a maximal inhibitory concentration ranging from 0.64 to 12.4 μM after 24 h incubation. Overall, LNPs are promising candidates for drug delivery applications, and the superparamagnetic behavior of FeO-LNPs makes them promising for cancer therapy and diagnosis, such as magnetic targeting and magnetic resonance imaging.
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http://dx.doi.org/10.1016/j.biomaterials.2016.12.034DOI Listing
March 2017

Tricyclic Benzo[cd]azulenes selectively inhibit activities of Pim kinases and restrict growth of Epstein-Barr virus-transformed cells.

PLoS One 2013 6;8(2):e55409. Epub 2013 Feb 6.

Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Finland.

Oncogenic Pim family kinases are often overexpressed in human hematopoietic malignancies as well as in solid tumours. These kinases contribute to tumorigenesis by promoting cell survival and by enhancing resistance against chemotherapy and radiation therapy. Furthermore, we have recently shown that they increase the metastatic potential of adherent cancer cells. Here we describe identification of tricyclic benzo[cd]azulenes and their derivatives as effective and selective inhibitors of Pim kinases. These compounds inhibit Pim autophosphorylation and abrogate the anti-apoptotic effects of Pim kinases. They also reduce cancer cell motility and suppress proliferation of lymphoblastoid cell lines infected and immortalized by the Epstein-Barr virus. Thus, these novel Pim-selective inhibitors provide promising compounds for both research and therapeutic purposes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055409PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566155PMC
December 2013

Synthesis and anti-leishmanial activity of heterocyclic betulin derivatives.

Bioorg Med Chem 2010 Feb 7;18(4):1573-82. Epub 2010 Jan 7.

Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Finland.

Betulin, a naturally occurring abundant triterpene is converted in four steps to 3,28-di-O-acetyllupa-12,18-diene. When various 4-substituted urazoles were oxidized to the corresponding urazines with iodobenzene diacetate in the presence of 3,28-di-O-acetyllupa-12,18-diene, new heterocyclic betulin derivatives were produced. These betulin derivatives were examined in a microplate assay at 50 microM for their ability to inhibit the growth of Leishmania donovani axenic amastigotes, a species that causes the fatal visceral leishmaniasis. GI(50) (concentration for 50% growth inhibition) values of the most effective compounds were determined and their cytotoxicity on the human macrophage cell line THP-1 evaluated. The anti-leishmanial activity on L. donovani amastigotes growing in macrophages was also examined. The heterocycloadduct between 3,28-di-O-acetyllupa-12,18-diene and 4-methylurazine was the most effective derivative with an GI(50)=8.9 microM against L. donovani amastigotes.
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http://dx.doi.org/10.1016/j.bmc.2010.01.003DOI Listing
February 2010

Enzyme-assisted synthesis and structure characterization of glucuronic acid conjugates of losartan, candesartan, and zolarsartan.

Bioorg Chem 2008 Jun 1;36(3):148-55. Epub 2008 Apr 1.

Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, PO Box 56 (Viikinkaari 5 E), FIN 00014, Finland.

Three angiotensin II receptor antagonists--losartan, candesartan, and zolarsartan--were investigated. All the compounds, which are structural analogues, are metabolized via conjugation to glucuronic acid. Interestingly, both O- and N-glucuronidation take place, so that regioisomers are formed. One ether O-glucuronide, two acyl O-glucuronides, and five tetrazole-N-glucuronides were biosynthesized, in milligram scale, from the three sartan aglycones. Liver microsomes from bovine, moose, rat, and pig and recombinant human UDP-glucuronosyltransferases were used as catalysts. The synthesized compounds were identified as sartan glucuronides by mass spectrometry, while the sites of glucuronidation were determined by nuclear magnetic resonance spectroscopy. Drug metabolites are needed as standards for pharmaceutical research and, as the present study shows, they can easily be produced with enzymes as catalyst.
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http://dx.doi.org/10.1016/j.bioorg.2008.02.004DOI Listing
June 2008

Stereoselective aza Diels-Alder reaction on solid phase: a facile synthesis of hexahydrocinnoline derivatives.

J Comb Chem 2007 Mar-Apr;9(2):263-6

Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, P. O. Box 56 (Viikinkaari 5 E), FI-00014 Helsinki, Finland.

As part of our continuing studies of polymer-supported pericyclic reactions for preparing biologically interesting heterocyclic compounds, we have introduced a traceless solid-phase synthesis of hexahydrocinnolines. We developed a method in which mild reaction conditions can be used for the hetero-Diels-Alder reactions on a polymeric support. The dienoic 3-vinyl-2-cyclohexenol attached to a Wang resin through an ether linkage undergoes [4 + 2] cycloaddition reaction with several azadienophiles. The highly stereoselective Diels-Alder reaction showed preferential formation of a single cycloadduct resulting from an anti attack of the dienophile on the polymer-bound diene. Trifluoroacetic acid-mediated cleavage of the polymer-bound cycloadducts yields fused nonaromatic hexahydrocinnolines in moderate yields in three steps.
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http://dx.doi.org/10.1021/cc060125lDOI Listing
May 2007

Enzyme-assisted synthesis and characterization of glucuronide conjugates of neuroactive steroids.

Steroids 2007 Mar 23;72(3):287-96. Epub 2007 Jan 23.

Drug Discovery and Development Technology Center (DDTC), Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014 Helsinki, Finland.

Synthesis of reference standards is needed to determine the presence and function of steroid glucuronides in the brain or other tissues, because commercial sources of steroid glucuronide standards are limited or unavailable. In the present study porcine, rat, and bovine liver microsomes were tested to evaluate their ability to glucuronidate eight neurosteroids and neuroactive steroids of various types: dehydroepiandrosterone, pregnenolone, isopregnanolone, 5alpha-tetrahydrodeoxycorticosterone, corticosterone, cortisol, beta-estradiol, and testosterone. In general, the glucuronidation efficiency of rat liver was rather poor compared with that of bovine and porcine liver microsomes. Since porcine liver apparently has a relatively large amount of dehydrogenase, its microsomes also produced dehydrogenated steroids and their glucuronides, as well as various regioisomers in which the site of glucuronidation varied. In contrast, bovine liver microsomes produced mainly a single major glucuronidation product and few dehydrogenation products and gave the best overall yield for two-third of the steroids tested. The enzymatic synthesis of five glucuronides of four steroids was carried out and the conditions, purification, and analytical methods for the glucuronidation products were optimized. The steroid glucuronides synthesized were characterized by nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography-mass spectrometry (LC-MS). The stereochemically pure steroid glucuronide conjugates were recovered in milligram amounts (yield 10-78%) and good purity (>85-90%), which is sufficient for LC-MS/MS method development and analyses of steroid glucuronides in biological matrices such as brain, urine, or plasma.
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http://dx.doi.org/10.1016/j.steroids.2006.11.023DOI Listing
March 2007

The Diels-Alder reaction between deactivated dienes and electron-deficient dienophiles on solid support: stereoselective synthesis of hexahydro-1,3-dioxoisoindoles.

J Comb Chem 2004 Mar-Apr;6(2):283-5

Viikki Drug Discovery Technology Center, Department of Pharmacy, P.O. Box 56 (Viikinkaari 5 E), FIN-00014 University of Helsinki, Finland.

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http://dx.doi.org/10.1021/cc030114hDOI Listing
May 2004