- An efficient and practical method for the synthesis of mono-N-protected α,ω-diaminoalkanes
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The large-scale synthesis of mono-N-protected (Cbz, Boc, Ts, and Ns) α,ω-diaminoalkanes (the number of carbon atoms=3, 4, 5 and 6) are accomplished in 81-94% yield by the protection of amine and subsequent reduction of an azido group from α,ω-azido alkyl amines. α,ω-Azido alkyl amines are prepared efficiently by the partial reduction of α,ω-diazidoalkanes which are obtained from the corresponding dibromoalkanes.
- Lee, Jae Wook,Jun, Sung Im,Kim, Kimoon
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- Azido-Desferrioxamine Siderophores as Functional Click-Chemistry Probes Generated in Culture upon Adding a Diazo-Transfer Reagent
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This work aimed to undertake the in situ conversion of the terminal amine groups of bacterial desferrioxamine (DFO) siderophores, including desferrioxamine B (DFOB), to azide groups to enable downstream click chemistry. Initial studies trialed a precursor-directed biosynthesis (PDB) approach. Supplementing Streptomyces pilosus culture with blunt-end azido/amine non-native substrates designed to replace 1,5-diaminopentane as the native diamine substrate in the terminal amine position of DFOB did not produce azido-DFOB. Addition of the diazo-transfer reagent imidazole-1-sulfonyl azide hydrogen sulfate to spent S. pilosus medium that had been cultured in the presence of 1,4-diaminobutane, as a viable native substrate to expand the suite of native DFO-type siderophores, successfully generated the cognate suite of azido-DFO analogues. CuI-mediated or strain-promoted CuI-free click chemistry reactions between this minimally processed mixture and the appropriate alkyne-bearing biotin reagents produced the cognate suite of 1,4-disubstituted triazole-linked DFO-biotin compounds as potential molecular probes, detected as FeIII-loaded species. The amine-to-azide transformation of amine-bearing natural products in complex mixtures by the direct addition of a diazo-transfer reagent to deliver functional click chemistry reagents adds to the toolbox for chemical proteomics, chemical biology, and drug discovery.
- Gotsbacher, Michael P.,Codd, Rachel
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p. 1433 - 1445
(2020/02/27)
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- Comparative Studies of Three Pairs of α- And γ-Conjugated Folic Acid Derivatives Labeled with Fluorine-18
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The folate receptor (FR) is upregulated in various epithelial cancer types (FR α-isoform), while healthy tissues show only restricted expression. FR-targeted imaging using folate radiopharmaceuticals is therefore a promising approach for the detection of FR-positive cancer tissue. Almost all folate-based radiopharmaceuticals have been prepared by conjugation at the γ-carboxylic functionality of the glutamate moiety of folic acid. In this work, three pairs of fluorinated α- and γ-conjugated folate derivatives were synthesized and their in vitro and in vivo properties compared. The syntheses of all six regioisomers were obtained in good chemical yields using a multistep synthetic approach including the highly selective Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radiosyntheses of the α- and γ-conjugated 18F-labeled folate derivatives were accomplished in moderate to good radiochemical yields, high radiochemical purities (>95%), and specific activities ranging from 25 to 196 GBq/μmol. In vitro, all folate derivatives showed high binding affinity to the FR-α (IC50 = 1.4-2.2 nM). In vivo PET imaging and biodistribution studies in FR-positive KB tumor-bearing mice demonstrated similar FR-specific tumor uptake for both regioisomers of each pair of compounds. However, FR-unspecific liver uptake was significantly lower for the α-regioisomers compared to the corresponding γ-regioisomers. In contrast, kidney uptake was up to 50% lower for the γ-regioisomers than for the α-regioisomers. These results show that the site of conjugation in the glutamyl moiety of folic acid has a significant impact on the in vivo behavior of 18F-based radiofolates, but not on their in vitro FR-binding affinity. These findings may potentially stimulate new directions for the design of novel 18F-labeled folate-based radiotracers.
- Boss, Silvan D.,Betzel, Thomas,Müller, Cristina,Fischer, Cindy R.,Haller, Stephanie,Reber, Josefine,Groehn, Viola,Schibli, Roger,Ametamey, Simon M.
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- Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies
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Outbreaks of acute gastroenteritis caused by noroviruses constitute a public health concern worldwide. To date, there are no approved drugs or vaccines for the management and prophylaxis of norovirus infections. A potentially effective strategy for the development of norovirus therapeutics entails the discovery of inhibitors of norovirus 3CL protease, an enzyme essential for noroviral replication. We describe herein the structure-based design of the first class of permeable, triazole-based macrocyclic inhibitors of norovirus 3C-like protease, as well as pertinent X-ray crystallographic, biochemical, spectroscopic, and antiviral studies.
- Weerawarna, Pathum M.,Kim, Yunjeong,Kankanamalage, Anushka C. Galasiti,Damalanka, Vishnu C.,Lushington, Gerald H.,Alliston, Kevin R.,Mehzabeen, Nurjahan,Battaile, Kevin P.,Lovell, Scott,Chang, Kyeong-Ok,Groutas, William C.
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p. 300 - 318
(2016/07/06)
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- Synthesis, biological activity and structural study of new benzotriazole-based protein kinase CK2 inhibitors
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A new series of 4,5,6,7-tetrabromobenzotriazole (TBB) derivatives was synthesized and characterized as CK2 inhibitors. They were readily synthesized using a click chemistry approach based on a Cu(i)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). Some of the synthesized compounds present interesting inhibitory activities using an in vitro assay, with Ki values in the low micro molar range and a high degree of selectivity against a panel of 24 kinases. Selected compounds were tested for their antiproliferative effect on several cancer cell lines, and for their proapoptotic activity towards human Jurkat T-leukemia and MCF-7 breast adenocarcinoma cells, showing that they can be proposed as promising anticancer agents. Docking studies as well as crystallographic analysis allowed us to identify ligand-CK2 interactions that account for the molecular recognition process, and can help to further optimize this family of compounds as CK2 inhibitors.
- Swider,Maslyk,Zapico,Coderch,Panchuk,Skorokhyd,Schnitzler,Niefind,De Pascual-Teresa,Ramos
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p. 72482 - 72494
(2015/09/15)
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- 18 F-LABELLED FOLATES
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The present invention is directed towards new 18F-folate radiopharmaceuticals, wherein fluorine-18 is covalently linked through a triazole- or tetrazole linker to a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of therapy of cancer and inflammatory and autoimmune diseases.
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Page/Page column 42
(2008/12/08)
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- NOVEL AZALIDE AND AZALACTAM DERIVATIVES AND PROCESS FOR THE PRODUCTION OF THE SAME
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A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, which is useful for a prophylactic and/or therapeutic treatment of a microbial infectious disease. [R1 is hydrogen atom, or a linear C1-6 alkylcarbonyl group; R2 is hydrogen atom, or a C1-6 alkylcarbonyl group; R3 is hydrogen atom, a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkenyl group, a C2-6 alkenylcarbonyl group, a C2-6 alkynyl group, or an Ar-B- group (Ar represents an aryl group, or a heterocyclic group, and B is a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C2-6 alkenyl group, a C2-6 alkenylcarbonyl group, or a C2-6 alkynyl group); R5, R6, R7, and R8 represent hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or an Ar-B'- group (B' is a C1-6 alkyl group, a C2-6 alkenyl group, or a C2-6 alkynyl group); X is oxygen atom, or an -NR4- group (R4 is hydrogen atom, a C1-6 alkyl group, or a C1-6 alkyl group which may be substituted with an Ar group); and R4' is hydrogen atom, or a group represented by the aforementioned formula (a) (R3" and R4" represent hydrogen atom, or a linear or branched C1-6 alkylcarbonyl group)]
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Page/Page column 40
(2010/11/08)
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- Mono-Protected Diamines. Nα-tert-Butoxycarbonyl α,ω-Alkanediamine Hydrochlorides from Amino alcohols.
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Nα-tert-Butoxycarbonyl α,ω-alkanediamine hydrochlorides 3a-e are prepared from the amino alcohols in yields of 66-87percent.Reaction of the free amine with di-tert-butyl dicarbonate gives the N-tert-Butoxycarbonylamino alcohol 1a-e.One-pot conversion to the azide 2a-e via the mesylate under phase-transfer conditions followed by hydrogenolysis in the presence of chloroform yields the title compounds.
- Mattingly, Phillip G.
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p. 366 - 368
(2007/10/02)
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