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On the basis of potent anti-HCV activity of2'-C-methy1adenosme, novel 2'-C-hydroxymethy1adenosine analogues 2a-c were synthesized from D-ribose in order to lead to favorable interaction with HCV polymerase. Among compounds tested, adenosine derivative 2a exhibited potent anti-HCV activity, indicating that the hydroxyl group of 2'-C-hydroxymethyl substituent led to favorable interaction with HCV polymerase. ⓒ 2006 Elsevier Ltd. All rights reserved.
The objectives of this study were to develop an ammonolysis-based microencapsulation technique using a nonhalogenated isopropyl formate and to evaluate its feasibility in preparing poly-D,L-lactide-co-glycolide microspheres. The choice of isopropyl formate was based on its great reactivity toward ammonolysis and acceptance as a flavoring agent for human food by regulatory agencies. Progesterone was used as a model drug for microencapsulation. In the practice of this microencapsulation process, a dispersed phase consisting of isopropyl formate, the polymer and progesterone was emulsified in an aqueous phase. Solvent removal from emulsion droplets was rapidly achieved by ammonolysis at ambient conditions, not by typical solvent evaporation and/or extraction. Depending upon microsphere formulations, its encapsulation efficiency ranged from 88.0+/-3.6 to 97.0+/-3.6%. Analysis of FTIR spectra suggested that there were no significant chemical interactions between prednisolone and the polymer. Both DSC and XRD data substantiated that the magnitude of an actual progesterone loading influenced its physical status in the microspheres. Interestingly, the microspheres prepared in this study contained noticeably lower levels of solvent residues: a gas chromatographic analysis demonstrated that the levels of residual isopropyl formate found in different microspheres were not more than 0.34+/-0.07%. It was seen to be feasible from these results that the ammonolysis-based approach using isopropyl formate might have a potential as an alternative microencapsulation technique.
Lee, Hyun-Jung,Kim, Jin-Sung,Suh, Myung-Eun,Park, Hyen Joo,Lee, Sang Kook,Rhee, Hee-Kyung,Kim, Hwa Jung,Seo, Eun-Kyung,Kim, Choonmi,Lee, Chong-Ock,Choo Park, Hea-Young 이화여자대학교 약학연구소 2008 藥學硏究論文集 Vol.- No.18
The substituted pyridazino[4,5-b]phenazine-5,12-diones and tri/tetra-azabenzo[a]fluorene-5,6-diones were synthesized from 6,7-dichloroph-thalazine-5,8-dione and 6,7-dichloroquinoline-5,8-dione, respectively. The cytotoxic activities of the prepared compounds were evaluated by an SRB (Sulforhodamine B) assay against the following human cancer cell lines: A549 (lung), SK-0V-3 (ovarian), SK-MEL-2 (melanoma), XF 498 (CNS), and HCT 15 (colon). Almost all synthesized pyridazino[4,5-b]phenazine-5,12-diones (7a-j) presented higher cytotoxicity than that of doxorubicin (IC_(50) = 0.097-0.225 μM) against the cancer cell lines, In particular, the cytotoxicity of compounds 7f (R₁=Et) and 7h (R₁, R₂ = Me) against all human cancer cell lines examined was about 10 times higher than that of doxorubicin. However, the cytotoxicities of several synthesized azabenzo[a]fluorene-5,6-diones (12a, 12c, 12d, 12e, and 12g) against the cancer cell lines in vitro were comparable to those of doxorubicin.
With an aim to mimic natural extracellular matrix, we fabricated the nano- and microfibrous matrix with chitosan by electrospinning nanofibers onto predefined microfibrous mesh for effective chondrocytes cultivation. Rolling the double-layered nano-/microfibrous membranes produced three-dimensional (3-D) scaffolds that exhibited the interconnected open pore structure in their scanning electron microscopy images. In vitro chondrocyte culture experiment showed that this nano-/microfibrous 3-D matrix provided a significantly greater microenvironment for chondrocytes to proliferate and produce glycosaminoglycan as compared with only microfibrous 3-D matrix. This difference could be explained by the result on 2-D membrane, where chitosan nanofibrous surface substantially facilitated the cellular attachment and proliferation, and efficiently prevented phenotypic changes of chondrocytes, when compared with chitosan microfibrous membrane and film. In this regard, the nano-/microfibrous 3-D matrix we fabricated in this study would possess a great potential as a system for effective chondrocyte cultivation and also for application to cartilage regeneration therapy.
A series of4(5)-(6-alkylpyridin-2-yl)imidazoles 13a-p, 17a, and 17b have been synthesized and evaluated for ALK5 inhibitory activity in an enzyme assay and in cell-based luciferase reporter assays. The quinoxalinyl analogue 13e inhibited ALK5 phosphorylation with an IC_(50) of 0.012 μM and showed more than 90% inhibition at 0.05 μM in a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct. The binding mode of 13e generated by flexible docking studies shows that 13e fits well into the active site cavity of ALK5 by forming several tight interactions.
Piroxicam can be ionized as a zwitterion that has two pKa values (pKa_(1) = 1.86 and pKa_(1) = 5.46). Consequently, piroxicam has a low solubility in both polar and nonpolar media, and a low lipophilicity, which results in a low permeability. Three piroxicam-ethanolamine salts were prepared, which had a higher area under the curve (AUC) than piroxicam. There were minimal differences in the AUC among the salt forms. It was reported that the piroxicam triethanolamine salt had a lower permeability across the::kin than piroxicam but it had a higher oral bioavaitability. Piroxicam monoethanolamine showed the highest C_(max) followed by piroxicam diethanolamine and piroxicam Iriethanolarnine. The dissolution rates of piroxicam and its salts were similar at pH 1.2. Piroxicam monoethanolamine showed the highest dissolution rate at pH 6.8, which was followed by the piroxicam diethanolamine and piroxicam triethanolarnine salts. The order of dissolution rate at pH 6.8 matched the order of C_(max) or the AUC after oral administration.
2-Aminothiazolo[5,4-b]pyridines and 2-aminobenzoxazoles have been synthesized from 2-hydroxy-3-thioureidopyridine and 2-hydroxy-3-thioureidobenzene respectively via acid catalyzed cyclization, which were prepared by the reaction of isothiocyanates with 2-hydroxy-3-aminopyridine or 2-aminophenol, The hydroxyl group of N-(2-hydroxy-5-phenyl)- N'-phenyl thiourea reacted as nucleophile to thioureido carbon to give 2-aminobenzoxazoles, whereas that of N-(2-hydroxypyridino)-N'-Phenylthiourea was reacted as leaving group upon nuclephillic sulfur of thiourea group in the presence of trifluoroacetic acid or phosphoric acid.
The transforming growth factor-β(TGF-β) plays a central role in the progression of renal fibrosis. TGF-β transduces its signal through the activin receptor-like kinase (ALK)5. IN-1130, a novel small molecule ALK5 inhibitor, inhibited the purified kinase domain of ALKS-mediated Smad3 phosphorylation with an IC_(50) value of 5.3 nM. IN-1130 proved to be highly selective in a panel of 27 serine/threonine and tyrosine kinases including p38α mitogen-activated protein kinase. We evaluated the efficacy of IN-1130 to block renal fibrogenesis induced by unilateral ureteral obstruction (UUO) in rats. Either vehicle (saline) or IN-1130 (10 and 20mg/kg/ day) was intraperitoneally administered to UUO rats for 7 and 14 days. Phosphorylated Smad2 (PSmad2) and markers of fibrosis were analyzed in kidney tissues, In UUO control kidneys, interstitial fibrosis including tubular atrophy, loss and dilation, inflammatory cell infiltration, and fibroblast cell proliferation was prominent. These morphological changes were notably reduced by 1N-1130 treatment. IN-1130 decreased levels of TGF-/β1 messenger RNA (mRNA), type I collagen mRNA, and pSmad2, compared to UUO control rats. As determined by measuring the hydroxyproline content, total kidney collagen amount was increased in UUO control kidneys, but significantly reduced by IN-1130 treatment, which was comparable to results of histochemical staining for collagen. IN-1130 also suppressed the expression of a-smooth muscle actin (a-SMA) and fibronectin in UUO kidneys. Our results show that IN-1130 suppressed the fibrogenic process of UUO, further underscoring the potential clinical benefits of IN-1130 in the treatment of renal fibrosis.
Three new phenolic compounds, (E)-4'-demethyl-6-methyleucomin (1), anemarcoumarin A (2), and anemarchalconyn (3), were isolated from an ethyl acetate extract of the rhizomes of Anemarrhena asphodeloides, together with seven known compounds (4-10). The structures of the new compounds (1-3) were determined on the basis of spectroscopic data interpretation. Compound 3 exhibited a potent inhibitory effect against the differentiation of preadipocyte 3T3-L1 cells with an IC50 value of 5.3 microM.
Nucleoside diphosphate kinase (NDPK, Nm23), a housekeeping enzyme, is known to be a multifunctional protein, acting as a metastasis suppressor, transactivation activity on c-myc, and regulating endocytosis. The cellular mechanisms regulating Nm23 functions are poorly understood. In this study, we identified the modifications and interacting proteins of Nm23-H1 in response to oxidative stress. We found that Cys109 in Nm23-H1 is oxidized to various oxidation states including intra- and inter-disulfide crosslinks, glutathionylation, and sulfonic acid formation in response to H(2)O(2) treatment both in vivo and in vitro. The cross-linking sites and modifications of oxidized Nm23-H1 were identified by peptide sequencing using UPLC-ESI-q-TOF tandem MS. Glutathionylation and oxidation of Cys109 inhibited the NDPK enzymatic activity of Nm23-H1. We also found that thioredoxin reductase 1 (TrxR1) is an interacting protein of Nm23-H1, and it binds specifically to oxidized Nm23-H1. Oxidized Nm23 is a substrate of NADPH-TrxR1-thioredoxin shuttle system, and the disulfide crosslinking is reversibly reduced and the enzymatic activity is recovered by this system. Oxidation of Cys109 in Nm23-H1 inhibited its metastatic suppressor activity as well as the enzymatic activities. The mutant, Nm23-H1 C109A, retained both the enzymatic and metastasis suppressor activities under oxidative stress. This suggests that key enzymatic and metastasis suppressor functions of Nm23-H1 are regulated by oxido-reduction of its Cys109.