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排序方式: 共有65条查询结果,搜索用时 15 毫秒
1.
Peng L Mundada L Stomel JM Liu JJ Sun J Yet SF Fay WP 《Antioxidants & redox signaling》2004,6(4):729-735
Heme oxygenase-1 (HO-1) plays a key role in protecting tissue from oxidative stress. Although some studies implicate HO-1 in modulating thrombosis after vascular injury, the impact of HO-1 on the rate of clot formation in vivo is poorly defined. This study examined the potential function of HO-1 in regulating platelet-dependent arterial thrombosis. Platelet-rich thrombi were induced in C57BL/6J mice by applying 10% ferric chloride to the exposed carotid artery. Mean occlusion time of wild-type mice (n = 10) was 14.6 +/- 1.0 min versus 12.9 +/- 0.6 min for HO-1-/- mice (n = 11, p = 0.17). However, after challenge with hemin, mean occlusion time was significantly longer in wild-type mice (16.3 +/- 1.2 min, n = 15) than HO-1-/- mice (12.0 +/- 1.0 min, n = 9; p = 0.021). Hemin administration induced an approximately twofold increase in oxidative stress, measured as plasma thiobarbituric acid reactive substances. Immunohistochemical analysis revealed that hemin induced a robust increase in HO-1 expression within the carotid arterial wall. Ex vivo blood clotting within a collagen-coated perfusion chamber was studied to determine whether the accelerated thrombosis observed in HO-1-/- mice was contributed to by effects on the blood itself. Under basal conditions, mean clot formation during perfusion of blood over collagen did not differ between wild-type mice and HO-1-/- mice. However, after hemin challenge, mean clot formation was significantly increased in HO-1-/- mice compared with wild-type controls. These results suggest that, under basal conditions, HO-1 does not exert a significant effect on platelet-dependent clot formation in vivo. However, under conditions that stimulate HO-1 production, platelet-dependent thrombus formation is inhibited by HO-1. Enhanced HO-1 expression in response to oxidative stress may represent an adaptive response mechanism to down-regulate platelet activation under prothrombotic conditions. 相似文献
2.
Heme oxygenase-1 promotes neovascularization in ischemic heart by coinduction of VEGF and SDF-1 总被引:2,自引:0,他引:2
Lin HH Chen YH Chang PF Lee YT Yet SF Chau LY 《Journal of molecular and cellular cardiology》2008,45(1):44-55
Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with multiple protective functions in cardiovascular systems. Studies have shown that the timely cardiac HO-1 overexpression at acute phase of ischemic infarction (MI) provides protection via its anti-apoptotic and anti-inflammatory effects. Here we demonstrate that a delayed HO-1 transduction mediated by a recombinant adeno-associated virus in ischemic hearts of mice with permanent coronary artery ligation significantly attenuated left ventricular fibrosis and cardiac dysfunctions examined at 4 weeks post MI. HO-1-mediated protection was correlated with enhanced vascularization in the ischemic myocardium. HO-1 gene transfer resulted in a notable increase in the number of c-kit+- stem cells recruited to the infarcted area at 10 days after ligation. HO-1-mediated stem cell recruitment was also demonstrated in the heart of non-ischemic mice receiving intravenous infusion of green fluorescent protein-bearing bone marrow stem cells. Additional experiments revealed that vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were highly induced in HO-1 transduced myocardium. Mononuclear cell infiltration was evident and colocalized with angiogenic factors in the same region. Flow cytometry analysis of the mononuclear cells isolated from HO-1-transduced left ventricles revealed that over 50% of cells expressed CD34, a marker of hematopoietic stem cells and endothelial progenitor cells. VEGF and SDF-1 blockade by neutralizing antibodies significantly attenuated HO-1-mediated neovascularization and protection in infarcted mice. These data suggest that cardiac HO-1 gene transfer post MI provides protection at least in part by promoting neovascularization through inducing angiogenic factors and the recruitment of circulating progenitor/stem cells. 相似文献
3.
研究70%肝切除对大鼠胎肝细胞脾内移植后增殖影响。分离孕3周SD大鼠胚胎肝细胞,将其移植入70%肝切除大鼠脾内,分别于移植后7天和30天应用流式细胞仪分析肝切除大鼠残肝细胞的细胞周期,用图像分析法检测脾内移植肝细胞面积密度。与对照组比较,胎肝细胞移植后7天,肝切除鼠残细胞S期细胞比例明显增加(P<0.05),Gz/M期细胞比例明显减少(P<0.01)。而其牌内移植 胎肝细胞面积密度则显著升高(P<0.05);30天后,残 细胞再生状态与移植胎肝细胞的面积密度与对照组比较均无显著性差异。研究表明,70%肝切除的肝再生有利于大鼠肝细胞脾内移植后的增殖。 相似文献
4.
Relapsed and late-onset Nipah encephalitis 总被引:3,自引:0,他引:3
Tan CT Goh KJ Wong KT Sarji SA Chua KB Chew NK Murugasu P Loh YL Chong HT Tan KS Thayaparan T Kumar S Jusoh MR 《Annals of neurology》2002,51(6):703-708
An outbreak of infection with the Nipah virus, a novel paramyxovirus, occurred among pig farmers between September 1998 and June 1999 in Malaysia, involving 265 patients with 105 fatalities. This is a follow-up study 24 months after the outbreak. Twelve survivors (7.5%) of acute encephalitis had recurrent neurological disease (relapsed encephalitis). Of those who initially had acute nonencephalitic or asymptomatic infection, 10 patients (3.4%) had late-onset encephalitis. The mean interval between the first neurological episode and the time of initial infection was 8.4 months. Three patients had a second neurological episode. The onset of the relapsed or late-onset encephalitis was usually acute. Common clinical features were fever, headache, seizures, and focal neurological signs. Four of the 22 relapsed and late-onset encephalitis patients (18%) died. Magnetic resonance imaging typically showed patchy areas of confluent cortical lesions. Serial single-photon emission computed tomography showed the evolution of focal hyperperfusion to hypoperfusion in the corresponding areas. Necropsy of 2 patients showed changes of focal encephalitis with positive immunolocalization for Nipah virus antigens but no evidence of perivenous demyelination. We concluded that a unique relapsing and remitting encephalitis or late-onset encephalitis may result as a complication of persistent Nipah virus infection in the central nervous system. 相似文献
5.
6.
Ryan Q. Tran Seth A. Jacoby Kaitlyn E. Roberts William A. Swann Nekoda
W. Harris Long P. Dinh Emily L. Denison Larry Yet 《RSC advances》2019,9(31):17778
3-Aryl-2-phosphinoimidazo[1,2-a]pyridine ligands were synthesized from 2-aminopyridine via two complementary routes. The first synthetic route involves the copper-catalyzed iodine-mediated cyclizations of 2-aminopyridine with arylacetylenes followed by palladium-catalyzed cross-coupling reactions with phosphines. The second synthetic route requires the preparation of 2,3-diiodoimidazo[1,2-a]pyridine or 2-iodo-3-bromoimidazo[1,2-a]pyridine from 2-aminopyridine followed by palladium-catalyzed Suzuki/phosphination or a phosphination/Suzuki cross-coupling reactions sequence, respectively. Preliminary model studies on the Suzuki synthesis of sterically-hindered biaryl and Buchwald–Hartwig amination compounds are presented with these ligands.3-Aryl-2-phosphoimidazo[1,2-a]pyridine ligands were prepared via two complimentary synthetic routes and were evaluated in the Suzuki–Miyaura and Buchwald–Hartwig amination cross-coupling reactions.Palladium-catalyzed cross-coupling reactions have revolutionized the formation of C–C and C–X bond formation in the academic and industrial synthetic organic chemistry sectors.1,2 Applications such as synthesis of natural products,3 active pharmaceutical ingredients (API),4 agrochemicals,5 and materials for electronic applications6 are showcased. Snieckus described in his 2010 Nobel Prize review that privileged ligand scaffolds represented the “third wave” in the cross-coupling reactions where the “first wave” was the investigation of the metal catalyst-the rise of palladium and the “second wave” was the exploration of the organometallic coupling partner.1 In the last twenty years, it was recognized that the choice of ligand facilitated the oxidative addition and reductive-elimination steps of the catalytic cycle of transition metal-catalyzed cross-coupling reactions, increasing the overall rate of the reaction. For example, bulky trialkylphosphines facilitated the oxidative addition processes of electron-rich, unactivated substrates such as aryl chlorides.7,8 Sterically demanding ligands also provided enhanced rates of reductive elimination from [(L)nPd(aryl)(R), R = aryl, amido, phenoxo, etc.] species by alleviation of steric congestion.9 Privileged ligands such as Buchwald''s biarylphosphines,10,11 Fu''s trialkylphosphines,7,8,12 Nolan–Hermann''s N-heterocyclic carbenes (NHC),13–15 Hartwig''s ferrocenes,16,17 Beller''s bis(adamantyl)phosphines18,19 and N-aryl(benz)imidazolyl or N-pyrrolylphosphines,20,21 Zhang''s ClickPhos ligands,22,23 and Stradiotto''s biaryl P–N phosphines,24,25 to mention a few, have found wide-spread use in Suzuki–Miyaura, Corriu–Kumada, Heck, Negishi, Sonogashira, C–X (X = S, O, P) cross-coupling and Buchwald–Hartwig amination reactions (Fig. 1). Preformed catalysts with these ligands attached to the palladium metal center are also recognized as well-defined entities in cross-coupling reactions.26Open in a separate windowFig. 1Privileged ligands for palladium-catalyzed cross-coupling reactions.The term privileged structure was first coined by Evans et al. in 1988 and was defined as “a single molecular framework able to provide ligands for diverse receptors”.27 In the last three decades, it is clear that privileged structures are exploited as opportunities in drug discovery programs.28–31 For example, imidazo[1,2-a]pyridines are privileged structures in medicinal chemistry programs (Fig. 2).32 Imidazo[1,2-a]pyridines are a represented motif in several drugs on the market such as zolpidem, marketed as Ambien™ for the treatment of insomnia,33 minodronic acid, marketed as Bonoteo™ for oral treatment of osteoporosis,34 and olprinone, sold as Coretec™ as a cardiotonic agent.35Open in a separate windowFig. 2Imidazo[1,2-a]pyridines as privileged structures in medicinal chemistry and in our cross-coupling reactions approach.Our group is interested in a long-term research program directed at the use of key privileged structures that are employed in drug discovery programs as potential phosphorus ligands for cross-coupling reactions. In our entry into the use of privileged structures from the medicinal chemistry literature for our investigation into new phosphorus ligands, we have developed two complementary synthetic routes for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands from 2-aminopyridine as our initial substrate.Our first synthetic route for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l required the copper(ii) acetate iodine-mediated double oxidative C–H amination of 2-aminopyridine (1) with arylacetylenes under an oxygen atmosphere to give 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d (Scheme 1).36,37Open in a separate windowScheme 1Preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l from 2-aminopyridine via copper-catalyzed arylacetylene cyclizations/palladium-catalyzed phosphination reactions sequences.Phenylacetylene and 2-/3-/4-methoxyphenylacetylenes were commercially available reagents. With intermediates 2a–d in hand, we explored several cross-coupling phosphination reactions and we found that palladium-catalyzed phosphination with DIPPF ligand in the presence of cesium carbonate as the base in 1,4-dioxane under reflux provided twelve new ligands 3a–3l as shown in 38 Moderate to good yields were obtained under these cross-coupling conditions. There are few commercially available dimethoxyphenylacetylenes, and most are prohibitively expensive, and so an alternative synthetic strategy was explored.Palladium-catalyzed phosphination of 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2da
Open in a separate windowaReaction conditions: 2a–2d (1 equiv.), HPR2 (1 equiv.), Pd(OAc)2 (2 mol%), Cs2CO3 (1.2 equiv.), DIPPF (2.5 mol%), 1,4-dioxane, 80 °C.2-Iodoimidazo[1,2-a]pyridine (4) was conveniently prepared in three steps from 2-aminopyridine (1) following literature procedures, which was then converted into either iodo 5 or bromo 6 with NIS or NBS, respectively (Scheme 2).39,40Open in a separate windowScheme 2Preparation of 2,3-diiodoimidazo[1,2-a]pyridine (5) and 3-bromo-2-iodoimidazo[1,2-a]pyridine (6).When the phosphorus ligands 3 contained tert-butyl or cyclohexyl groups, method 1 was followed where 2,3-diiodoimidazo[1,2-a]pyridine (5) underwent Suzuki cross-coupling reactions with arylboronic acids to yield aryl intermediates 7a–7f, which was followed by palladium-catalyzed cross-coupling phosphination reactions with di-tert-butylphosphine or dicyclohexylphosphine to give C-2 substituted phosphorus ligands 3m–3u in low to moderate yields (Scheme 3, 38 The phosphorus ligands 3v–3ab were prepared from 3-bromo-2-iodoimidazo[1,2-a]pyridine (6) via a palladium-catalyzed phospination with diphenylphosphine (method 2) to give intermediate 8 (X = Br, I becomes PPh2) followed by Suzuki palladium-catalyzed cross-coupling reactions with arylboronic acids. Note that the change in reactivity of the core when switching between bromo and iodo at C3 results in a change in the order of cross-coupling steps.Open in a separate windowScheme 3Preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3m–3ab from 2-iodo-3-iodo(or bromo)imidazo[1,2-a]pyridines 5 or 6via palladium-catalyzed Suzuki/phosphination or a phosphination/Suzuki cross-coupling reactions sequences.Palladium-catalyzed Suzuki/phosphination or phosphination/Suzuki reactions sequences of 2,3-diiodoimidazo[1,2-a]pyridine (5) or 3-bromo-2-iodoimidazo[1,2-a]pyridine (6)a
Open in a separate windowaReaction conditions: 5, ArB(OH)2, Pd(PPh3)4 (5 mol%), Na2CO3 (2 equiv.), 1,4-dioxane/H2O (2 : 1) and HPR2 (1 equiv.), Pd(OAc)2 (2.5–5 mol%), Cs2CO3 (1.2 equiv.), DIPPF (2.5–10 mol%), 1,4-dioxane, 80 °C or 6, reverse sequence of reactions.With our library of functionalized imidazo[1,2-a]pyridine phosphorus ligands 3a–3ab in hand, we began to screen these ligands in Suzuki–Miyaura cross-coupling reactions to prepare sterically-hindered biaryl compounds. We chose the Suzuki–Miyaura cross-coupling reactions of m-bromo-xylene (9) and 2-methoxyphenylboronic acid (10) to give 2,6-dimethyl-(2-methoxy)biphenyl (11) as our model reaction as outlined in ii) acetate with 2.5 equivalents of base in 1,4-dioxane at 80 °C for 12–24 h. As expected, SPhos and XPhos were employed as our initial ligands to confirm our GC analyses of >99% conversion in our chosen model reaction (Entries 14–15). With the GC conditions validated, we screened selected ligands from 3a–3ab. It was clearly evident that the di-tert-butyl phosphorus ligands represented by 3a, 3m, and 3p were ineffective ligands in our model reactions (Entries 1–3). Furthermore, the diphenyl phosphorus ligands such as 3w, 3y, 3z, and 3ab showed low to moderate conversions in the model cross-coupling reactions (Entries 6–9). However, the dicyclohexyl phosphorus ligands shown by 3r and 3t showed greater than 99% conversions by GC analyses (Entries 4–5). Further exploration of ligand 3r with K3PO4 as the base, stirring the reaction overnight at room temperature or for 3 h at 80 °C showed inferior conversions (Entries 10–12). There was no conversion when a ligand was not used in the model reaction (Entry 13).Optimization of conditions for the Suzuki–Miyaura cross-coupling model reaction
Open in a separate windowaBased on GC analyses of consumed 9.bIsolated yield of 96% was obtaisned.Furthermore, a Buchwald–Hartwig amination model study was investigated with our new imidazo[1,2-a]pyridine phosphorus ligands 3a–3ab. The Buchwald–Hartwig amination reaction of 4-chlorotoluene (12) with aniline (13) to give 4-methyl-N-phenylaniline (14) was screened with our ligands ( Entry Ligand Conditions Conversiona (%) 1 3a 38 2 3d 26 3 3e >99 b 4 3g 29 5 3h 54 6 3k 71 7 3n 0 8 3p 0 9 3q >99 10 3r 92 11 3s >99 12 3s K3PO4 was used as base 83 13 3s K2CO3 was used as base 0 14 3s KOt-Bu was used as base >99 15 3s NaOt-Bu was used as base >99
Entry | Ar | R | 3 (% yield) |
---|---|---|---|
1 | Ph (2a) | t-Bu | 3a (41) |
2 | Ph (2a) | Cy | 3b (50) |
3 | Ph (2a) | Ph | 3c (61) |
4 | 2-OMeC6H4 (2b) | t-Bu | 3d (53) |
5 | 2-OMeC6H4 (2b) | Cy | 3e (83) |
6 | 2-OMeC6H4 (2b) | Ph | 3f (69) |
7 | 3-OMeC6H4 (2c) | t-Bu | 3g (62) |
8 | 3-OMeC6H4 (2c) | Cy | 3h (72) |
9 | 3-OMeC6H4 (2c) | Ph | 3i (79) |
10 | 4-OMeC6H4 (2d) | t-Bu | 3j (73) |
11 | 4-OMeC6H4 (2d) | Cy | 3k (55) |
12 | 4-OMeC6H4 (2d) | Ph | 3l (59) |
Entry | R | Ar | Method/substrate | Step 1 (% yield) | Step 2 (% yield) |
---|---|---|---|---|---|
1 | t-Bu | 2,3-diOMeC6H3 | 1, 5 | 7a (59) | 3m (64) |
2 | t-Bu | 3,4-diOMeC6H3 | 1, 5 | 7b (54) | 3n (31) |
3 | t-Bu | 2,5-diOMeC6H3 | 1, 5 | 7c (58) | 3o (61) |
4 | t-Bu | 3,4,5-triOMeC6H2 | 1, 5 | 7d (50) | 3p (62) |
5 | Cy | 2,3-diOMeC6H3 | 1, 5 | 7a (59) | 3q (46) |
6 | Cy | 2,6-diOMeC6H3 | 1, 5 | 7e (40) | 3r (52) |
7 | Cy | 3,4-diOMeC6H3 | 1, 5 | 7b (54) | 3s (52) |
8 | Cy | 2,3,4-triOMeC6H2 | 1, 5 | 7f (58) | 3t (21) |
9 | Cy | 3,4,5-triOMeC6H2 | 1, 5 | 7d (50) | 3u (55) |
10 | Ph | 2,3-diOMeC6H3 | 2, 6 | 8 (70) | 3v (52) |
11 | Ph | 2,5-diOMeC6H3 | 2, 6 | 8 (70) | 3w (68) |
12 | Ph | 3,4-diOMeC6H3 | 2, 6 | 8 (70) | 3x (67) |
13 | Ph | 2,3,4-triOMeC6H2 | 2, 6 | 8 (70) | 3y (52) |
14 | Ph | 3,4,5-triOMeC6H2 | 2, 6 | 8 (70) | 3z (64) |
15 | Ph | 4-FC6H4 | 2, 6 | 8 (70) | 3aa (40) |
16 | Ph | 3-F,5-OMeC6H3 | 2, 6 | 8 (70) | 3ab (39) |
Entry | Ligand | Conditions | Conversiona (%) |
---|---|---|---|
1 | 3a | 12 | |
2 | 3m | 20 | |
3 | 3p | 14 | |
4 | 3r | >99 b | |
5 | 3t | >99 | |
6 | 3w | 21 | |
7 | 3y | 55 | |
8 | 3z | 46 | |
9 | 3ab | 11 | |
10 | 3r | K3PO4 was used as base reaction was performed at 25 °C reaction was stirred for 3 h no ligand | 91 |
11 | 3r | 4 | |
12 | 3r | 39 | |
13 | — | 0 | |
14 | SPhos | >99 | |
15 | XPhos | >99 |