Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitomycin C (1) is the prototypical bioreductive alkylating agent. Studies have shown that mitomycin C and its derivatives selectively alkylate guanine residues within di- and trinucleotide DNA sequences. This investigation sought to improve the selective DNA bonding properties of the mitomycins by coupling them with antisense oligodeoxynucleotides. Two procedures were developed that allowed the attachment of a phosphorothioate oligodeoxynucleotide containing a hexylamino spacer at the 5' terminus with a C(10)-activated mitomycin. In the first procedure, decarbamoylation of 1 (NaOCH3/ benzene) afforded 10-decarbamoylmitomycin C (10), which was treated with either dimethyl sulfate or methylthiochloroformate and base to yield 10-decarbamoylporfiromycin (11) and N(1a)-[(methylthio)-carbonyl]-10-decarbamoylmitomycin C (12), respectively. Activation of the C(10) site in 11 and 12 with 1,1'-carbonyldiimidazole or with 1,1'-thiocarbonyldiimidazole provided the N(1a)-substituted mitomycin 10-decarbamoyl-10-O-carbonylimidazoles (5, 7) and 10-decarbamoyl-10-O-thiocarbonylimidazoles (6, 8), respectively. Compounds 5-8 were reacted with glycine methyl ester hydrochloride (17) and base in both methylene chloride and aqueous buffered solutions to determine the ease and efficiency in which these C(10)-activated mitomycin derivatives coupled to amines. It was found that 5-8 all reacted with 17 in methylene chloride to give the coupled products 18-21 but that improved amine coupling yields in water were observed for the 10-decarbamoyl-10-O-thiocarbonylimidazoles 6 and 8 as compared with the 10-decarbamoyl-10-O-carbonylimidazoles 5 and 7. This finding led to the coupling of the phosphorothioate oligodeoxynucleotide, H2N(CH2)6-P(S)(OH)-GGCCCCGTG-GTGGCTCCAT (22) to 8. Compound 22 complemented a 19-base sequence in the translation initiation region of the human A-raf-1 gene. Use of excess 8 (28 equiv) with 22 gave only a 36% yield of the coupled product 23, which proved difficult to separate from 22. In the second procedure, phosphorothioate oligodexynucleotides that contained a hexylamino spacer at the 5'termini were coupled to 10-des(carbamoyloxy)-10-isothiocyanatoporfiromycin (9). Compound 9 was prepared in four steps from 11. Mesylation (methanesulfonyl chloride/pyridine) of 11 gave the C(10) mesylate 13, which was then treated with NaN3 (dimethylformamide, 90 degrees C) to give 10-des(carbamoyloxy)-10-azidoporfiromycin (14). Catalytic reduction (PtO2, H2) of 14 in pyridine afforded C(10) amine 15. Treatment of 15 with di-2-pyridyl thionocarbonate provided the desired 10-des(carbamoyloxy)-10-isothiocyanatoporfiromycin (9). Compound 9 readily coupled with 17 and base in both methylene chloride and aqueous buffered solutions to give 25. Use of the 5'hexylaminophosphorothioate oligodeoxynucleotides 32-35 in place of 17 gave the conjugated adducts 28-31, respectively, in a 12% to near-quantitative yield. The products were purified by semipreparative HPLC. Antisense agents 28-31 were designed to target a 30-base-long region from the coding region of the human FGFR1 gene. One adduct, 29, reduced the number of FGFR1 receptors in human aortic smooth cells for bFGF on the cell surface, which suggested down-regulation of FGFR1 gene expression. Further, 29 inhibited cultured human aortic smooth muscle cell proliferation and was less cytotoxic than porfiromycin (2). The biological assay data suggest that the phosphorothioate oligodexynucleotide porfiromycin conjugates may be more target selective and less toxic than either mitomycin or porfiromycin and thus be promising therapeutic agents.
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PMID:Design, synthesis, and evaluation of mitomycin-tethered phosphorothioate oligodeoxynucleotides. 895 Apr 85

In the mouse, mutations at the natural resistance-associated macrophage protein 1 (Nramp1) gene abrogate resistance to infection with antigenically unrelated intracellular parasites such as Mycobacterium, Salmonella, and Leishmania. Nramp1 expression is restricted to reticuloendothelial organs and peripheral blood leukocytes, where the protein may function as a membrane transporter of an as yet to be identified substrate. To identify the human blood cell type(s) expressing NRAMP1 mRNA and determine how Nramp1 expression is regulated in these cells, we have examined separated populations of peripheral blood leukocytes and in vitro cell lines. We observed that polymorphonuclear leukocytes (PMN) are the major site of NRAMP1 expression, followed to a lesser degree by monocytes (MN). Migration of MN to tissues (alveolar macrophages) or maturation in vitro (long-term culture) was associated with a higher level of NRAMP1 expression compared with blood MN. Northern analyses of RNA from model cultured cells showed absence of NRAMP1 expression in transformed cell lines from either erythroid or lymphoid T or B lineages as well as progenitors of the monocyte/macrophage pathway (KG1, U937, THP1), and the HL-60 promyelocytic leukemia. Induction of differentiation of HL-60 cells toward either the monocyte/macrophage (vitamin D3, phorbol ester) or the granulocyte pathways (DMF, DMSO), as measured by induction of IL8-Rb, c-FMS, and CD14 marker gene expression, was concomitant with a strong induction of NRAMP1 expression. These results suggest that NRAMP1 expression is specific to the myeloid lineage and is acquired during the maturation of PMN and MN. The possibility that NRAMP1 may be a component of the phagosomal/endosomal apparatus common to PMN and MN is discussed.
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PMID:Expression of the human NRAMP1 gene in professional primary phagocytes: studies in blood cells and in HL-60 promyelocytic leukemia. 900 May 42

The HIV-1 long terminal repeat (LTR) introduced into the macrophage cell line THP-1 and the T lymphocyte cell line Jurkat in association with the luciferase reporter gene is activated by the polar, aprotic solvents dimethylsulfoxide (DMSO), dimethylacetamide (DMAC), and dimethylformamide (DMF). These solvents also greatly potentiated the activation of the LTR in THP-1 cells by phorbol myristate acetate (PMA), tumor necrosis factor alpha (TNF-alpha), H202, and a Staphylococcus epidermidis product. Lipopolysaccharide (LPS) and lipoteichoic acid (LTA) at 1 microg/ml had no effect on the LTR in THP-1 cells unless the solvents were added. The aprotic solvents also greatly potentiated the activation of the LTR in Jurkat cells by PMA, TNF-alpha, and H202, whereas LPS, LTA, or the S. epidermidis product had no effect in the presence or absence of the solvents. DMSO, DMAC, and DMF also increased the production of intact virions by latently HIV-1-infected ACH-2, J1.1, U1, and OM10.1 cells under some experimental conditions. The use of the polar aprotic solvents DMSO, DMAC, and DMF, by amplification, may allow the better detection of a weak activator of the LTR and facilitate studies of the mechanism of activation.
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PMID:Activation of the HIV type 1 long terminal repeat and viral replication by dimethylsulfoxide and related solvents. 931 Feb 89

A series of 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas were prepared and evaluated as inhibitors of the FGF receptor-1 tyrosine kinase. Condensation of 4,6-diaminonicotinaldehyde and substituted phenylacetonitriles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectively gave the 2-ureas in varying yields (23-93%). For the preparation of more soluble 7-alkylamino-2-ureas, a number of protecting groups for the 2-amine were evaluated (phthaloyl, 4-methoxybenzyl) following selective blocking of the 7-amine (trityl), but these were not superior to the (required) 2-tert-Bu-urea group itself. Direct alkylation of the anion of the (unprotected) 7-amino group with excess 4-(3-chloropropyl)morpholine in DMF gave low (10%) yields of the desired product, but alkylation of the 7-acetamido anion, followed by mild alkaline hydrolysis, raised this to 64%. 3-Phenyl analogues were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine kinases, whereas 3-(2,6-dichlorophenyl) analogues were most effective against c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selectivity for FGFR alone. A water-soluble (7-morpholinylpropylamino) analogue retained high FGFR potency (IC(50) 31 nM) and selectivity. Pairwise comparison of the 1, 6-naphthyridines and the corresponding known pyrido[2,3-d]pyrimidine analogues showed little differences in potency or patterns of selectivity, suggesting that the 1-aza atom of the latter is not important for activity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tumor cell lines and was particularly potent against HUVECs (IC(50) 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC(50) 0.01 nM) and Matrigel invasion (IC(50) 7 nM) and showed significant in vivo antitumor effects in a highly vascularized mammary adenocarcinoma 16/c model at nontoxic doses. The compounds are worthy of further evaluation as antiangiogenesis agents.
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PMID:3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and related 2-urea derivatives are potent and selective inhibitors of the FGF receptor-1 tyrosine kinase. 1106 16

Poly(epsilon-caprolactone)/poly(ethylene glycol) (abbreviated as CE) diblock copolymers were synthesized to make core-shell type nanoparticles for all-trans-retinoic acid (atRA). Fluorescence spectroscopy showed that critical association concentration (CAC) value decreased at higher MW of CE diblock copolymer. Drug loading characteristics were studied under various experimental conditions. Drug contents and loading efficiency increased as the MW of poly(epsilon-caprolactone) (PCL) block of CE and initial drug feeding amount increased. Solvent used and preparation method also affected drug contents and loading efficiency. According to 1H NMR using CDCl3 and D2O, specific peaks of the PCL block and drug appearing in CDCl3, disappeared at D2O, suggesting hydrophobic core with hydrophilic shell formed in water. atRA release was faster at smaller MW of copolymer and lower drug contents. Nanoparticles prepared in DMF showed faster release rate compared with those prepared in THF or acetone. Cytotoxicity of atRA against U87MG, U251MG and U343MG cell lines were increased by nanoencapsulation while empty nanoparticles of CE diblock copolymer were not significantly affected.
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PMID:All-trans-retinoic acid release from core-shell type nanoparticles of poly(epsilon-caprolactone)/poly(ethylene glycol) diblock copolymer. 1501 Jan 34

According to our "block-copolymer-free" strategy for self-assembly of polymers, noncovalently connected micelles (NCCM) with poly(epsilon-caprolactone) (PCL) as the core and poly(acrylic acid) (PAA) as the shell in aqueous solutions were attained due to specific interactions between the component polymers. The micellar structure was then locked in by the reaction of PAA with diamine. Afterward, hollow spheres based on PAA network were obtained by either core degradation with lipase or core dissolution with dimethylformamide of the cross-linked micelles. The cavitation process was monitored by dynamic light scattering, which indicated a mass decrease and size expansion. The hollow structure is confirmed by transmission electron microscopy observations. The resultant hollow spheres are pH- and salt-responsive: there is a substantial volume increase when pH changes from acid to base, and vice versa. The volume change takes place dramatically over the pH-range from 5.8 to 7.5. Furthermore, this volume-pH-dependence is found to be completely reversible provided the effect of ionic strength is excluded. The volume change can be adjusted by changing the shell thickness and the cross-linking degree of the hollow spheres. The salt effect on the hollow sphere size depends on pH: with increasing salt concentration the size shows an increase, a decrease, and a little change in acidic, basic, and neutral media, respectively.
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PMID:pH-responsive core-shell particles and hollow spheres attained by macromolecular self-assembly. 1569 4

Gold nanoparticles of improved stability against aggregation were prepared using poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) star-block copolymers. A five-arm star-shaped macroinitiator (PEO) was utilized for the automated parallel controlled ring-opening polymerization of epsilon-caprolactone to prepare a series of PEO-b-PCL star-block copolymers with a constant PEO core linked to PCL blocks of variable length. The PEO core was swelled with KAuCl4 in N,N-dimethylformamide (DMF), and gold nanoparticles were subsequently obtained by reduction with NaBH4. Since the process was always templated by the same PEO core for all investigated polymers, the average dimension of the formed gold nanoparticles was in the same range for all star-block copolymers. In sharp contrast, the size distribution and long-term stability against aggregation of the gold nanoparticles dispersed in DMF were strongly dependent on the PCL block length, confirming the role of PCL blocks as stabilizing blocks for these nanoparticles.
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PMID:Star-block copolymers as templates for the preparation of stable gold nanoparticles. 1608 12

This article reports on a novel two-step strategy for the coating of cardiovascular stents by strongly adhering biocompatible and biodegradable aliphatic polyesters. First, a precoating of poly(ethylacrylate) (PEA) was electrografted onto the metallic substrate by cathodic reduction of the parent monomer in dimethylformamide (DMF). The electrodeposition of PEA, in a good solvent of it, was confirmed by both Infra-red and Raman spectroscopies. The pendant ester groups of PEA were then chemically reduced into aluminum alkoxides, able to initiate the ring-opening polymerization (ROP) of either D,L-lactide (LA) or epsilon-caprolactone (CL). Growth of biodegradable PLA or PCL coatings from the adhering precoating was confirmed by both Infra-red and Raman spectroscopies, and directly observed by scanning electron microscopy (SEM). This type of coating can act as an anchoring layer for the subsequent casting of drug-loaded polyester films allowing the controlled release of antiproliferative agents for the treatment of in-stent restenosis.
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PMID:Surface modification of metallic cardiovascular stents by strongly adhering aliphatic polyester coatings. 1631 21

The aim of this study was to prepare non-woven materials from a biodegradable polymer, poly(epsilon-caprolactone) (PCL) by electrospinning. PCL was synthesized by ring-opening polymerization of epsilon-caprolactone in bulk using stannous octoate as the catalyst under nitrogen atmosphere. PCL was then processed into non-woven matrices composed of nanofibers by electrospinning of the polymer from its solution using a high voltage power supply. The effects of PCL concentration, composition of the solvent (a mixture of chloroform and DMF with different DMF content), applied voltage and tip-collector distance on fiber diameter and morphology were investigated. The diameter of fibers increased with the increase in the polymer concentration and decrease in the DMF content significantly. Applied voltage and tip-collector distance were found critical to control 'bead' formation. Elongation-at-break, ultimate strength and Young's modulus were obtained from the mechanical tests, which were all increased by increasing fiber diameter. The fiber diameter significantly influenced both in vitro degradation (performed in Ringer solution) and in vivo biodegradation (conducted in rats) rates. In vivo degradation was found to be faster than in vitro. Electrospun membranes were more hydrophobic than PCL solvent-casted ones; therefore, their degradation was a much slower process.
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PMID:In vitro and in vivo degradation of non-woven materials made of poly(epsilon-caprolactone) nanofibers prepared by electrospinning under different conditions. 1636 36

Biodegradable elastomeric network polyesters were prepared from multifunctional aliphatic carboxylic acids such as tricarballylic acid (Yt) or meso-1,2,3,4-butanetetracarboxylic acid (Xb) and poly(epsilon-caprolactone) (PCL) diols with molecular weights of 530, 1,250 and 2,000 g.mol-1. Prepolymers prepared by a melt polycondensation were cast from DMF solution and postpolymerized at 280 degrees C for various periods of times to form a network. The resultant films were transparent, flexible and insoluble in organic solvents. The network polyesters obtained were characterized by IR absorption spectra, WAXS, density measurement, DSC, and tensile test. YtPCL1250, and XbPCL1250 network polyester films showed good elastomeric properties with high ultimate elongation (540-590%), and low Young's modulus (2.5-3.3 MPa). The enzymatic degradation was estimated by the weight loss of network films in a buffer solution with Rhizopus delemar lipase at 37 degrees C. The degree and rate of degradation were significantly affected by the molecular weight of PCL diol, chemical structures of multifunctional aliphatic carboxylic acids and the morphology of network films. The changes in the solid states of network films during the degradation were also estimated by the results of DSC and WAXS. [see text]
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PMID:Biodegradable network elastomeric polyesters from multifunctional aliphatic carboxylic acids and poly(epsilon-caprolactone) diols. 1667 79


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