BACKGROUND & AIMS: :Direct-acting antiviral (DAA) agents specifically target viral proteins. Two DAAs have been already been approved for the treatment of HCV infection and many more are in development. DAA treatment of HCV infection, however, leads to the selection of viral variants (produced by the error-prone HCV polymerase) that are resistant to the DAA agent in use. The selection of DAA-resistant HCV variants has been studied extensively in vitro and in vivo. Common amino acid substitution sites in each of the non-structural proteins are associated with DAA-resistance: D168, A155, A156 and V36 in NS3 protease; L31 and Y93 in NS5A; S282, S96, P495, M423, M414 and C316 in NS5B. In this review we cover the basic principles of DAA resistance, summarise the available resistance data for the various classes of DAAs and discuss the potential of DAA combination therapy for overcoming DAA-resistance, resulting in major advances in the treatment of HCV.

背景与目标： : 直接作用抗病毒 (DAA) 药物专门针对病毒蛋白。已经批准了两种daa用于治疗HCV感染，并且还有更多的daa正在开发中。但是，对HCV感染的DAA治疗导致选择对使用中的DAA试剂具有抗性的病毒变体 (由易错的HCV聚合酶产生)。抗DAA HCV变体的选择已在体外和体内进行了广泛研究。每个非结构蛋白中常见的氨基酸取代位点与DAA抗性相关: NS3蛋白酶中的D168，A155，A156和V36; NS5A中的L31和Y93; NS5B中的S282，S96，P495，M423，M414和C316。在这篇综述中，我们涵盖了DAA耐药的基本原理，总结了各类DAA的可用耐药数据，并讨论了DAA联合疗法克服DAA耐药的潜力，从而在HCV治疗方面取得了重大进展。

BACKGROUND & AIMS: :Mammalian cells respond to their substrates by complex changes in gene expression profiles, morphology, proliferation and migration. We report that substrate nanotopography alters morpohology and proliferation of human embryonic stem cells (hESCs). Fibronectin-coated poly(di-methyl siloxane) substrates with line-grating (600nm ridges with 600nm spacing and 600+/-150nm feature height) induced hESC alignment and elongation, mediated the organization of cytoskeletal components including actin, vimentin, and alpha-tubulin, and reduced proliferation. Spatial polarization of gamma-tubulin complexes was also observed in response to nanotopography. Furthermore, the addition of actin disrupting agents attenuated the alignment and proliferative effects of nanotopography. These findings further demonstrate the importance of interplay between cytoskeleton and substrate interactions as a key modulator of morphological and proliferative cellular response in hESCs on nanotopography.

背景与目标： : 哺乳动物细胞通过基因表达谱，形态，增殖和迁移的复杂变化来响应其底物。我们报告了底物纳米照相改变了人类胚胎干细胞 (hESCs) 的形态和增殖。具有线光栅 (600nm脊具有600nm间距和600 +/-150nm特征高度) 的纤连蛋白包被的聚 (二-甲基硅氧烷) 基底诱导hESC排列和伸长，介导包括肌动蛋白、波形蛋白和 α-微管蛋白在内的细胞骨架组分的组织，并降低增殖。响应纳米照相，还观察到 γ-微管蛋白复合物的空间极化。此外，肌动蛋白破坏剂的加入减弱了纳米照相的排列和增殖作用。这些发现进一步证明了细胞骨架与底物相互作用之间的相互作用作为纳米照相hESCs中形态和增殖细胞反应的关键调节剂的重要性。

BACKGROUND & AIMS: :The 7-azaindenoisoquinolines are cytotoxic topoisomerase I (Top1) inhibitors. Previously reported representatives bear a 3-nitro group. The present report documents the replacement of the potentially genotoxic 3-nitro group by 3-chloro and 3-fluoro substituents, resulting in compounds with high Top1 inhibitory activities and potent cytotoxicities in human cancer cell cultures and reduced lethality in an animal model. Some of the new Top1 inhibitors also possess moderate inhibitory activities against tyrosyl-DNA phosphodiesterase 1 (TDP1) and tyrosyl-DNA phosphodiesterase 2 (TDP2), two enzymes that are involved in DNA damage repair resulting from Top1 inhibitors, and they produce significantly more DNA damage in cancer cells than in normal cells. Eighteen of the new compounds had cytotoxicity mean-graph midpoint (MGM) GI50 values in the submicromolar (0.033-0.630 μM) range. Compounds 16b and 17b are the most potent in human cancer cell cultures with MGM GI50 values of 0.063 and 0.033 μM, respectively. Possible binding modes to Top1 and TDP1were investigated by molecular modeling.

背景与目标： : 7-氮杂苯并异喹啉是细胞毒性拓扑异构酶I (Top1) 抑制剂。以前报道的代表带有3-硝基。本报告记录了用3-氯和3-氟取代基取代潜在的遗传毒性3-硝基，从而在人类癌细胞培养物中产生具有高Top1抑制活性和有效细胞毒性的化合物，并降低了动物模型中的致死率。一些新的Top1抑制剂对酪氨酸-DNA磷酸二酯酶1 (TDP1) 和酪氨酸-DNA磷酸二酯酶2 (TDP2) 也具有中等抑制活性，这两种酶参与了由Top1抑制剂产生的DNA损伤修复，并且它们在癌细胞中产生的DNA损伤明显多于正常细胞。18个新化合物的细胞毒性平均图中点 (MGM) GI50值在亚微摩尔 (0.033-0.630微米) 范围内。化合物16b和17b在MGM GI50值分别为0.063和0.033的人癌细胞培养物中是最有效的。通过分子建模研究了与Top1和tdp1的可能结合模式。

BACKGROUND & AIMS: :Suramin is a polyanionic compound currently used under evaluation for antineoplastic activity. One of the main problems encountered during clinical trials was an adverse neurotoxic effect, probably due to a direct cytotoxic effect on neural cells. Suramin is also known to trigger differentiation of human colon cancer cells, yet a chronic treatment induces a lysosomal storage disorder. The aim of this study was to evaluate suramin analogs for their effect: (i) on the lysosomal system of the human colon cancer cell clone HT29-D4; and (ii) on C6 glioma cell growth and morphology. One of the derivatives tested, NF036, induced terminal differentiation of HT29-D4 cells without any impairment of the lysosomal system. Furthermore, in contrast to suramin, NF036 did not alter C6 cell growth and morphology. We conclude that there is a relationship between the ability of a suramin derivative to induce a lysosomal storage disorder in human colon cancer cells and its neurotoxic effect. A double screening of suramin analogs on HT29-D4 and C6 cells allowed us to identify a new candidate antineoplastic drug: NF036.

背景与目标： : 苏拉明是目前用于抗肿瘤活性评估的聚阴离子化合物。在临床试验中遇到的主要问题之一是不良的神经毒性作用，可能是由于对神经细胞的直接细胞毒性作用所致。苏拉明还已知会触发人结肠癌细胞的分化，但长期治疗会导致溶酶体贮积障碍。这项研究的目的是评估苏拉明类似物的作用 :( i) 对人结肠癌细胞克隆HT29-D4的溶酶体系统; (ii) 对C6神经胶质瘤细胞的生长和形态。测试的衍生物之一NF036诱导了HT29-D4细胞的终末分化，而溶酶体系统没有任何损伤。此外，与苏拉明相反，NF036没有改变C6细胞的生长和形态。我们得出的结论是，苏拉明衍生物在人结肠癌细胞中诱导溶酶体贮积障碍的能力与其神经毒性作用之间存在关系。苏拉明类似物在HT29-D4和C6细胞上的双重筛选使我们能够鉴定一种新的候选抗肿瘤药物: nf036。

BACKGROUND & AIMS: :A set of benzophenone derivatives was evaluated for the antimalarial activity against Plasmodium berghei in mice and the mean survival time of mice for all the compounds was determined. The QSAR analysis was carried out for the fourteen benzophenone derivatives using different physicochemical descriptors. The multiple linear regression analysis was used to correlate the physicochemical descriptors with the antimalarial activity of the benzophenone derivatives from the training set and the best QSAR model was developed, which was further used to predict the antimalarial activity of other compounds from the class of benzophenones. To confirm the predictivity of the best QSAR model, a new set (test set) of six compounds was designed, synthesized and evaluated for the antimalarial activity. A good correlation between the experimental and predicted antimalarial activities was obtained for the test set compounds in the validation procedure, indicating the high predictivity of the developed QSAR model. Five benzophenone derivatives, which showed good antimalarial activity, were further studied for their drug-likeliness characteristic and per cent oral absorption using software "QikProp". It was observed that all the five benzophenone derivatives were found to be good drug candidates and showed good oral absorption.

背景与目标： : 评估了一组二苯甲酮衍生物对小鼠体内伯氏疟原虫的抗疟活性，并确定了所有化合物的小鼠平均存活时间。使用不同的物理化学描述符对14种二苯甲酮衍生物进行了QSAR分析。使用多元线性回归分析将物理化学描述符与训练集中的二苯甲酮衍生物的抗疟活性相关联，并开发了最佳QSAR模型，该模型进一步用于预测二苯甲酮类其他化合物的抗疟活性。为了确认最佳QSAR模型的预测性，设计，合成了一组新的六种化合物 (测试集)，并评估了其抗疟活性。在验证程序中，测试集化合物的实验活性与预测的抗疟活性之间具有良好的相关性，表明已开发的QSAR模型具有很高的预测性。使用软件 “QikProp” 进一步研究了五种具有良好抗疟活性的二苯甲酮衍生物的药物似然特性和口服吸收百分率。观察到所有五种二苯甲酮衍生物均被发现是良好的候选药物，并显示出良好的口服吸收。

BACKGROUND & AIMS: :A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and β-amyloid (Aβ) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042 μM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662 μM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aβ aggregation inhibition and antioxidant properties.

背景与目标： : 设计，合成和评估了一系列小檗碱-噻吩杂化物，作为乙酰胆碱酯酶 (AChE)，丁酰胆碱酯酶 (BuChE) 和 β-淀粉样蛋白 (A β) 聚集的抑制剂和抗氧化剂。在这些杂化物中，观察到化合物4f和4i，通过2-碳间隔物与o-甲基噻吩和o-氯噻吩连接的小檗碱是AChE的有效抑制剂，IC50值分别为0.077和0.042。在测试的化合物中，4i也是最有效的BuChE抑制剂，IC50值为0.662微米。AChE抑制剂复合物的动力学研究和分子建模模拟表明，这些小檗碱衍生物存在混合竞争结合模式。生物学研究还表明，这些杂种表现出有趣的活性，包括a β 聚集抑制和抗氧化特性。

BACKGROUND & AIMS: BACKGROUND:A possible negative role of pre-operative use of antitumour necrosis factor-alpha (anti-TNF-α) agents on post-operative outcomes in Crohn's disease (CD) patients is still debated. AIM:To examine the impact of pre-operative anti-TNF-α agents on post-operative outcomes 30 and 60 days after CD surgery in a nationwide Danish cohort. Outcomes were death, reoperation, anastomosis leakage, intra-abdominal abscess and bacteraemia. METHODS:We identified all patients having surgical procedures from 1 January 2000 to 31 December 2010 (n = 2293). Patients were classified according to use of anti-TNF-α agents within 12 weeks before surgery (exposed) or not (unexposed). Outcomes were obtained from nationwide registries and a bacteraemia registry. Sub-analyses were performed for bacteraemia and for impact of pre-operative timing of anti-TNF-α agents. RESULTS:Among surgical procedures for CD, 214 were exposed and 2079 were not. We found no increased relative risks of death or abscess drainage 30 or 60 days after follow-up. Among exposed, 7.5% had a reoperation within 30 days vs. 8.6% among unexposed, adjusted odds ratio (OR) = 0.92, 95% confidence interval (CI): 0.52-1.63. Among exposed, 3.8% had an anastomosis leakage within 30 days after surgery vs. 2.8% among unexposed, adjusted OR = 1.33, 95% CI: 0.59-3.02. No further cases of anastomosis leakages appeared within 60 days. Sub-analyses indicated no increased risk of bacteraemia after 30 days and no increased risks when anti-TNF-α agents were given ≤14 days before surgery. CONCLUSION:We found no significantly increased relative risks of post-operative complications after use of anti-TNF-α agents either 12 weeks or ≤14 days before surgery for Crohn's disease.

背景与目标：

BACKGROUND & AIMS: :NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.

背景与目标： : NO是大脑中重要的信使分子，在学习和记忆中起着重要作用，尤其是通过ERK/CREB信号通路。NO也是神经保护剂; 已经证明了多种机制可以促进细胞存活，因为随着衰老，抗氧化剂和营养因子的水平降低。模拟NO生物活性的小分子，包括NO供体，可以改善认知并提供神经保护。有几条证据表明，阿尔茨海默氏病的神经变性和痴呆特征与 β-淀粉样蛋白在alpha7-nicotinic乙酰胆碱受体上的作用有关。Abeta与通过ERK信号级联起作用的alpha7-nicotinic ACh受体的相互作用将影响突触可塑性和记忆的途径中的淀粉样蛋白级联反应和胆碱能假说联系起来。这种相互作用还提供了与AD中NO/cGMP信号传导中断的联系，此外，最近发现的直接证据表明Abeta下调了NO/cGMP/CREB途径。可溶性鸟苷酸环化酶的激活升高了大脑中的cGMP，代表了治疗AD和其他神经退行性疾病的治疗方法的核心要素，此外，有证据表明NO可能显示出不依赖cGMP的活性，并且可以通过多种生化信号传导途径起作用，以确保承受压力的神经元的存活。GT 1061是一种NO嵌合体，一种NO模拟化合物，包含辅助的，协同药效团，目前正在阿尔茨海默氏症的临床试验中。没有嵌合体和杂合硝酸盐有望作为具有多个作用位点的AD的治疗方法。

BACKGROUND & AIMS: OBJECTIVES:To assess the clinical effectiveness and cost-effectiveness of central venous catheters (CVCs) treated with anti-infective agents in preventing catheter-related bloodstream infection (CRBSI). DATA SOURCES:Major electronic databases were searched from 1985 to August 2005. REVIEW METHODS:The systematic clinical and economic reviews were conducted according to accepted procedures. Only full economic evaluations (synthesis of costs and benefits) comparing the use of anti-infective central venous catheters (AI-CVCs) with untreated CVCs or other treated catheters were selected for inclusion in the economic review. RESULTS:A total of 32 trials met the clinical inclusion criteria. Seven different types of AI-CVC were identified, with the most frequently tested being chlorhexidine and silver sulfadiazine (CHSS) (externally treated), CHSS (externally and internally treated) and minocycline rifampicin (internally and externally treated). In general, the trials were of a poor quality in terms of reported methodology, microbiological relevance and control of confounding variables. The pooled result suggests a statistically significant advantage for AI-CVCs in comparison to standard catheters in reducing CRBSI [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.34 to 0.60, 24 studies, I-squared = 0%, fixed effects]. Analysis by subgroups of catheters demonstrates that antibiotic-treated catheters and catheters treated internally and externally decrease CRBSI rates significantly (OR 0.26, 95% CI 0.15 to 0.46, six studies, I-squared = 0%, fixed effects, and OR 0.43, 95% CI 0.26 to 0.70, nine studies, I-squared = 0%, fixed effects, respectively). Catheters treated only externally demonstrate a wider CI and non-significant effect (OR 0.67, 95% CI 0.43 to 1.06, nine studies, I-squared = 0%, fixed effects). A treatment effect was also found for trials with an average duration of between 5 and 12 days, and for the one study with a mean duration of over 20 days. There was a statistically significant treatment effect for both femoral and jugular insertion sites and for those studies reporting a mix of insertion sites. The treatment effect was not observed in trials using exclusively subclavian insertion sites. Of the four trials that compared treated catheters, one reported a benefit of antibiotic-treated catheters over catheters treated externally with CHSS. All three sensitivity analyses testing for study design differences reported a statistically significant treatment effect. The review was limited owing to the quality of the trials included, marked differences in the definitions and methods of diagnosis of CRBSI, and inconsistent reporting of risk factors and patient population factors. Furthermore, two-thirds of trials were commercially funded. The economic performance (cost-effectiveness and potential cost-savings) of using AI-CVCs to reduce the number of CRBSIs in patients requiring a CVC was also reviewed. Results show that the use of AI-CVCs instead of standard CVCs can lead to a reduction in CRBSIs and decreased medical costs. To complement the reviews, a basic decision-analytic model was constructed to explore a range of possible scenarios for the NHS in England and Wales. Results show that for every patient who receives an AI-CVC there is an estimated cost-saving of 138.20 pounds. The multivariate sensitivity analyses estimate potentially large cost-savings, depending on the size of the population, under a wide range of cost and clinical assumptions. However, those considering the purchase of AI-CVCs should ensure that their patient populations and the important characteristics of local clinical practice are indeed similar to those described in this economic evaluation. CONCLUSIONS:Overall, AI-CVCs are clinically effective and relatively inexpensive and therefore their integration into clinical practice can be justified. However, the use of these anti-infective catheters without the appropriate use of other practical care initiatives will have only a limited success on the prevention of CRBSIs. Comparative trials are required to determine which, if any, of the treated catheters is the most effective. Pragmatic research related to the effectiveness of bundles of care that may reduce rates of CRBSI is also warranted.

背景与目标：

BACKGROUND & AIMS: :Five dichlorinated 8-quinolinols (2,5- 5,6-, 3,5-, 3,7-, and 4,5-dichloro-8-quinolinol) were tested against Candida albicans and C. tropicalis in Sabouraud dextrose broth with and without bovine serum. The 5,6-, 3,5-, and 3,7-dichloro-8-quinolinols proved to be more effective than the control, 5-fluorocytosine. In cytotoxicity tests employing baby hamster kidney (BHK) cells, all test agents proved to be more cytotoxic than the control. However, the minimum inhibitory concentration (MIC) of 3,5-dichloro-8-quinolinol to both fungi was only one tenth the cytotoxic dose, suggesting that the compound may be useful as a topical or systemic antifungal agent.

背景与目标： : 在具有和不具有牛血清的sabourad葡萄糖肉汤中，测试了五种二氯化的8-喹啉醇 (2,5- 5,6-，3,5-，3,7-和4,5-二氯-8-喹啉醇) 对白色念珠菌和热带假丝酵母。5,6-，3,5-和3,7-二氯-8-喹啉醇被证明比对照5-氟胞嘧啶更有效。在使用小仓鼠肾脏 (BHK) 细胞的细胞毒性测试中，所有测试剂均被证明比对照更具细胞毒性。然而，3,5-二氯-8-喹啉醇对两种真菌的最小抑制浓度 (MIC) 仅10分之1细胞毒性剂量，表明该化合物可用作局部或全身性抗真菌剂。

BACKGROUND & AIMS: BACKGROUND:Most dialysis patients receiving erythropoesis-stimulating agents (ESA) also receive parenteral iron supplementation. There are few data on the risk of hemosiderosis in this setting. METHODS:We prospectively measured liver iron concentration by means of T1 and T2* contrast magnetic resonance imaging (MRI) without gadolinium, in a cohort of 119 fit hemodialysis patients receiving both parenteral iron and ESA, in keeping with current guidelines. RESULTS:Mild to severe hepatic iron overload was observed in 100 patients (84%; confidence interval, [CI] 76%-90%), of whom 36% (CI, 27%-46%) had severe hepatic iron overload (liver iron concentration >201 μmol/g of dry weight). In the cross-sectional study, infused iron, hepcidin, and C-reactive protein values correlated with hepatic iron stores in both univariate analysis (P<.05, Spearman test) and binary logistic regression (P <.05). In 11 patients who were monitored closely during parenteral iron therapy, the iron dose infused per month correlated strongly with both the overall increase and the monthly increase in liver iron concentration (respectively, rho=0.66, P=.0306 and rho=0.85, P=0.0015, Spearman test). In the 33 patients with iron overload, iron stores fell significantly after iron withdrawal or after a major reduction in the iron dose (first MRI: 220 μmol/g (range: 60-340); last MRI: 50 μmol/g (range: 5-210); P <.0001, Wilcoxon's paired test). CONCLUSIONS:Most hemodialysis patients receiving ESA and intravenous iron supplementation have hepatic iron overload on MRI. These findings call for a revision of guidelines on iron therapy in this setting, especially regarding the amount of iron infused and noninvasive methods for monitoring iron stores.

背景与目标：

BACKGROUND & AIMS: :Topical application of 17 nmoles of the potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, resulted in a stimulation of the incorporation of [(3)H]lysine into epidermal histones. Maximum incorporation occurred 24 hr after treatment, concurrent with maximum DNA synthesis. The effects of phorbol and two phorbol esters on histone synthesis were related to their tumor-promoting activities. Treatment with hydroxyurea partially prevented the phorbol ester-induced stimulation of both DNA and histone synthesis, although it had no effect on the stimulation of protein synthesis. These findings are consistent with the likelihood that phorbol ester-induced epidermal histone synthesis is the result of a coupling between DNA synthesis and histone synthesis.

背景与目标： : 局部应用17 nmoles的有效肿瘤启动子，12-O-tetradecanoylphorbol-13-acetate，导致 [(3)H] 赖氨酸掺入表皮组蛋白的刺激。最大掺入发生在治疗后24小时，伴随着最大的DNA合成。佛波酯和两种佛波酯对组蛋白合成的影响与它们的促肿瘤活性有关。用羟基脲治疗部分阻止了佛波酯诱导的DNA和组蛋白合成的刺激，尽管它对刺激蛋白质合成没有影响。这些发现与佛波酯诱导的表皮组蛋白合成是DNA合成和组蛋白合成之间耦合的结果的可能性相一致。

BACKGROUND & AIMS: :The synthesis and antitumor activity in normoxic and hypoxic conditions of a series of pyrazolo[5,1-c][1,2,4]benzotriazine and its related analogues are reported. All compounds were tested on human colorectal adenocarcinoma cell line HCT-8 and for compounds 15 and 20, which show to have selective cytotoxicity in hypoxic and in normoxic conditions respectively, ROS production, cell cycle, and DNA fragmentation were measured. This preliminary study encouraged us to consider 15 and 20 as interesting leads for further optimization.

背景与目标： : 报道了一系列吡唑并 [5,1-c][1,2，4] 苯并三嗪及其相关类似物在常氧和低氧条件下的合成和抗肿瘤活性。所有化合物均在人大肠腺癌细胞系HCT-8上进行了测试，对于分别显示在低氧和常氧条件下具有选择性细胞毒性的化合物15和20，测量了ROS产生，细胞周期和DNA片段化。这项初步研究鼓励我们将15和20视为进一步优化的有趣线索。

BACKGROUND & AIMS: :A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77nM against chloroquine-resistant K1- and W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories.

背景与目标： : 通过改良的TMSN3-Ugi多组分反应合成了一系列新的基于脱氧阿莫地喹的化合物，并在体外评估了其抗血浆活性。最有效的化合物6b，6c和6j对抗氯喹的K1-和恶性疟原虫的W2-strains显示出IC50值在6-77nM范围内。frontrunner化合物6b和6c的体外ADME表征表明，这两种化合物可快速代谢，并在人和大鼠肝微粒体中具有较高的清除率。该结果与体内药代动力学研究密切相关，该研究表明6c在大鼠中的生物利用度低。通过lc-ms确定了初步的代谢物鉴定，并建议与叔氮相连的基团的代谢不正常。对6b和6c的初步研究表明，对主要的CYP450酶具有很强的抑制活性。在计算机对接研究中，用于合理化6c对CYP3A4的强抑制。我们的实验室目前正在对代谢物进行全面的表征和生物学评估。

BACKGROUND & AIMS: :Multidrug resistance (MDR) mediated by P-glycoprotein is one of the best characterized transporter-mediated barriers to successful cancer chemotherapy. In an attempt to find MDR-reversing agents, a series of novel acridine derivatives were synthesized and evaluated for their in vitro antiproliferative activities against K562 and K562/ADM cells. Some of these compounds showed superior MDR-reversing activities than Amsacrine, the reference compound. Structure-activity relationships (SAR) of these compounds indicated that the N, N-diethylamine moiety had an affect on the in vitro antiproliferative activity. Interestingly, the compounds bearing N, N-diethylamine moiety showed higher growth-inhibitory activity against K562/ADM cells than K562 cells. The high duplex DNA binding affinity and inhibition of topoisomerase of these acridine compounds are maintained which were confirmed by fluorescent quenching and DNA topoisomerase II cleavage assay, respectively. Moreover, several compounds were examined for their ability to increase the accumulation of rhodamine 123 in K562 and K562/ADM cells, and the result suggested that they may be inhibitors for P-glycoprotein. Our study suggested that acridine framework is a potentially interesting scaffold for developing novel MDR-reversing agents.

背景与目标： : 由P-糖蛋白介导的多药耐药性 (MDR) 是成功进行癌症化疗的最典型的转运蛋白介导的障碍之一。为了寻找MDR逆转剂，合成了一系列新型的a啶衍生物，并评估了它们对K562和K562/ADM细胞的体外抗增殖活性。这些化合物中的一些显示出比参考化合物Amsacrine更好的MDR逆转活性。这些化合物的构效关系 (SAR) 表明N，N-二乙胺部分对体外抗增殖活性有影响。有趣的是，带有N，N-二乙胺部分的化合物对K562/ADM细胞的生长抑制活性高于K562细胞。这些吖啶化合物的高双链DNA结合亲和力和拓扑异构酶的抑制作用得以维持，这分别通过荧光猝灭和DNA拓扑异构酶II裂解试验得到证实。此外，检查了几种化合物增加K562和K562/ADM细胞中罗丹明123积累的能力，结果表明它们可能是P-糖蛋白的抑制剂。我们的研究表明，a啶框架是开发新型MDR逆转剂的潜在有趣的支架。