BACKGROUND & AIMS: :New hydrazone derivatives were synthesized via the nucleophilic addition-elimination reaction of 2-[(1-methyl-1H-tetrazol-5-yl)thio)]acetohydrazide with aromatic aldehydes/ketones. The compounds were tested in vitro against various Candida species and compared with ketoconazole. Genotoxicity of the most effective anticandidal compounds was evaluated by umuC and Ames assays. All compounds were also investigated for their cytotoxic effects on NIH3T3 and A549 cell lines. Compound 8 was the most effective antifungal derivative against C. albicans (ATCC-90028) with a MIC value of 0.05 mg/mL. Compound 5 can be identified as the most promising anticancer agent against A549 cancer cell lines due to its inhibitory effect on A549 cell lines and low toxicity to NIH3T3 cells.

背景与目标： : 通过2-[(1-甲基-1h-四唑-5-基) 硫代)] 乙酰酰肼与芳族醛/酮的亲核加成消除反应合成了新的腙衍生物。对化合物进行了针对各种念珠菌的体外测试，并与酮康唑进行了比较。通过umuC和Ames分析评估了最有效的抗癌症化合物的遗传毒性。还研究了所有化合物对NIH3T3和A549细胞系的细胞毒性作用。化合物8是对白色念珠菌 (ATCC-90028) 最有效的抗真菌衍生物，MIC值为0.05 mg/ml。化合物5由于对A549细胞系的抑制作用和对NIH3T3细胞的低毒性，可被确定为最有前途的抗A549癌细胞系的抗癌剂。

BACKGROUND & AIMS: :Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.

背景与目标： : 烯基硼酸显示出重要的生物活性，有助于神经保护。我们已经确定了它们对 β-淀粉样蛋白 (β a) 聚集过程，β-分泌酶和乙胆碱酯酶在无细胞系统上的活性，对氧化还原和脂质过氧化状态以及对APPswe神经母细胞瘤细胞凋亡死亡的脆弱性的影响过氧化氢治疗之前和之后。我们发现2-芳基乙烯基硼酸及其某些酯具有一系列特性，这使它们作为影响AD中涉及的多个生物靶标的神经保护剂非常有用。这些性质与相关的2-芳基硼酸不平行。

BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

背景与目标： : 设计，合成和评估了一系列新型白藜芦醇衍生物，可作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中，化合物7l，(E)-5-(4-(异丙基氨基) 苯乙烯基) 苯-1,3-二醇表现出有效的 β-淀粉样蛋白聚集抑制活性，通过ThT荧光分析 (71.65% 在20μm) 和透射电子显微镜 (TEM) 证实了这一点。化合物7l也显示出良好的抗氧化活性 (在氧自由基吸收能力分析中4.12的Trolox当量和10μm细胞中活性氧的37% 减少)。化合物的细胞毒性分析7f，7i，7j和7l表明这些化合物在60μm时的毒性比白藜芦醇低。

BACKGROUND & AIMS: :In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.

背景与目标： : 在这项研究中，我们评估了新型八氢吡嗪 [2,1-a:5,4-a '] 二异喹啉衍生物 (1-7) 在MCF-7和MDA-MB-231乳腺癌细胞系中的细胞毒性和抗增殖能力。进行膜联蛋白V结合测定和线粒体电位破坏以确定细胞凋亡。与测试化合物孵育24小时后，测量了胱天蛋白酶3、8、9和10的活性，以解释诱导凋亡的详细分子机制。将实验结果与在喜树碱和依托泊苷存在下孵育后获得的效果进行了比较。我们的研究表明，在两种分析的乳腺癌细胞系中最具活性的化合物是化合物3和4。我们还观察到所有化合物均诱导细胞凋亡。我们证明了caspases 3、8、9和10的较高活性，这证实了凋亡的诱导与外部和内部细胞死亡途径有关。我们的研究表明，二异喹啉衍生物组中的新型化合物通过激活外在和内在凋亡途径在抗癌治疗中是有希望的候选者。

BACKGROUND & AIMS: :Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.

背景与目标： : 与微管蛋白结合并破坏微管动力学的抗肿瘤剂在过去几年中引起了极大的关注。为了扩展我们对噻唑环作为combretastatin A-4中存在的顺式烯烃的合适模拟物的了解，我们将3,4，5-三甲氧基苯基固定在噻唑核的C4-position。我们发现C2-和C5-positions的取代基对抗增殖活性具有深远的影响。比较噻唑环C5-position具有相同取代基的化合物，C2-position部分影响抗增殖活性，效力顺序为NHCH(3)> Me> N(CH(3))(2)。相对于C2-amino对应物，N-甲基氨基取代基显着提高了MCF-7细胞的抗增殖活性。从N-甲基氨基到N，N-二甲基氨基C2-position的空间体积增加导致活性降低1-2对数。2-n-甲基氨基噻唑衍生物3b，3d和3e是作为抗增殖剂的最具活性的化合物，其IC(50) 值从低微摩尔到个位数纳摩尔，此外，它们在多药耐药细胞系中也具有活性过表达P-糖蛋白。抗增殖活性可能是由化合物与微管蛋白聚合的秋水仙碱位点结合并破坏微管动力学引起的。此外，活性最高的化合物3e通过激活caspase-2，-3和-8诱导细胞凋亡，但3e并未引起线粒体去极化。

BACKGROUND & AIMS: :Phyto-psychopharmacological agents are extracts of plants with stimulating or calming effects on the central nervous system. Phyto-psycho-pharmacological agents are among the most commonly prescribed herbal medicines in Germany. The efficacy and harmlessness of some of the preparations have been established by high quality clinical trials. Between 1975 and 1992, a total of 34 clinical studies involving some 2326 patients were published on the effects of Ginkgo special extract EGb 761 and LI 1370; to date, 28 clinical trials in 2120 patients have been under-taken with alcoholic extracts of St. John's Wort. The therapeutic efficacy of kava and valerian extracts has been investigated in six and four controlled studies, respectively. In general, a high placebo effect is likely, which is why it is essential to include control groups in these studies. A considerable advantage over synthetic psychopharmacological agents is the low incidence of side effects, which in safety assessment studies is below 3%. The sharp increase in quality standards for clinical trials has meant that only a few preparations have undergone large scale testing programs in accordance with international guidelines. For other phyto-psychopharmacological agents, there is the danger that no further clinical trials will be undertaken due to the excessively high standards now demanded.

背景与目标： : 植物心理药物是对中枢神经系统具有刺激或镇静作用的植物提取物。植物心理药物是德国最常用的草药之一。一些制剂的疗效和无害化已通过高质量的临床试验确定。在1975年至1992年之间，共发表了34项临床研究，涉及约2326名患者，涉及银杏特殊提取物EGb 761和LI 1370的影响; 迄今为止，已对2120名患者进行了28项临床试验，其中包括圣约翰草的酒精提取物。卡瓦和缬草提取物的治疗功效已分别在六个和四个对照研究中进行了研究。一般来说，安慰剂效应可能很高，这就是为什么在这些研究中包括对照组是必不可少的。与合成精神药物相比，相当大的优势是副作用的发生率低，在安全性评估研究中，副作用的发生率低于3%。临床试验质量标准的急剧提高意味着只有少数制剂按照国际指南进行了大规模的测试计划。对于其他植物心理药物，由于现在要求的标准过高，因此存在无法进行进一步临床试验的危险。

BACKGROUND & AIMS: :Since there are no systematic studies available on the effects of anti-microtubule agents on ciliated protozoa, we screened a wide variety of such compounds for their effects on the growth of Paramecium tetraurelia cell cultures. Compounds tested include agents of widely different chemical composition and with reported effects on widely different cell types. We can differentiate between different drug effects: (a) Rotenone is the only agent without any recognisable effect, (b) Another group of compounds (including colchicine) requires very high concentrations, as compared to higher animal cells, i.e., rather close to a cytotoxic level; this group also includes tubulozole (unexpectedly without any difference between the cis- and the trans-stereoisomer). (c) A third group of drugs inhibits cell culture growth without any lethal effects (benzimidazoles, nocodazole, parbendazole; the [anti-]fungal antibiotic, griseofulvin; the herbicide, trifluralin). (d) Finally a group of agents are active in a concentration range also reported for plants (the herbicide, APM) or for higher animal cells (including the microtubule stabiliser, taxol) or for both (vinblastine, vincristine, triethyl lead), although they are cytotoxic at higher concentrations (like compounds of group [b]). Therefore, in particular compounds of group (c) and possibly of group (d) might be considered further on for a more detailed analysis of a possibly genuine anti-microtubular effect in Paramecium cells. Of particular interest may be nocodazole, parbendazole and trifluralin, since they can inhibit cell culture growth (over 24 h tested) in relatively low concentrations (comparable to other cell types) without any impairment of cell viability.

背景与目标： : 由于尚无关于抗微管剂对纤毛原生动物的影响的系统研究，因此我们筛选了各种此类化合物对草履虫四重草细胞培养物生长的影响。测试的化合物包括化学成分广泛不同的试剂，据报道对细胞类型广泛不同的影响。我们可以区分不同的药物作用 :( a) 鱼藤酮是唯一没有任何可识别作用的药物，(b) 与较高的动物细胞相比，另一组化合物 (包括秋水仙碱) 需要非常高的浓度，即相当接近细胞毒性水平; 该组还包括小管 (出乎意料的是，顺式和反式立体异构体之间没有任何区别)。(c) 第三组药物抑制细胞培养物的生长，而没有任何致死作用 (苯并咪唑，诺考达唑，帕苯达唑; [抗] 真菌抗生素灰黄霉素; 除草剂，氟拉林)。(d) 最后，一组试剂在植物 (除草剂，APM) 或高等动物细胞 (包括微管稳定剂，紫杉醇) 或两者 (长春碱，长春新碱，三乙基铅) 的浓度范围内具有活性，尽管它们在较高浓度下具有细胞毒性 (如 [b] 组的化合物)。因此，特别是可以进一步考虑 (c) 组和 (d) 组的化合物，以更详细地分析草履虫细胞中可能真正的抗微管作用。特别令人感兴趣的可能是诺考达唑，帕苯达唑和三氟拉林，因为它们可以在相对较低的浓度 (与其他细胞类型相当) 下抑制细胞培养物生长 (测试超过24小时)，而不会损害细胞活力。

BACKGROUND & AIMS: BACKGROUND:Intrauterine devices (IUDs) provide highly effective contraception for women worldwide. Reluctance to insert IUDs in the primary care setting may relate to concern about potential difficulty and complications, particularly in nulliparous women. AIMS:To determine the practitioner, patient and procedural factors associated with abandoned IUD insertion, practitioner-reported difficulty of insertion and adverse events during IUD insertions in the family planning setting. METHODS:This was a prospective study over a 12-month period of consecutive IUD insertions in four family planning clinics across New South Wales and Queensland. Patient, practitioner and device-related factors associated with abandoned IUD insertion, practitioner-reported ease of insertion and immediate insertion-related adverse events were analysed using logistic regression. RESULTS:Of 996 insertion procedures, successful insertion occurred in 95%, and 90% were reported as easy by the inserting doctor, including 80% of those in nulliparous women. Patient characteristics associated with an abandoned insertion were nulliparity (AOR 5.19; 2.49-10.82) or caesarean section-only deliveries (AOR 5.38; 2.58-11.22) and with practitioner-reported difficult insertion, nulliparity alone (AOR 1.98; 1.11-3.54). Practitioners inserting fewer than 100 IUDs over the 12-month study period more frequently rated insertions as difficult (AOR 1.76; 1.08-2.88). Complications occurred in 34 women and were more likely in nulliparous women (AOR 4.51; 2.16-9.39). CONCLUSIONS:Most IUDs can be successfully inserted, even in nulliparous women, in a primary care setting. Referral to a specialist may be appropriate for some women who are nulliparous or had caesarean section-only deliveries, depending on the experience of the practitioner.

背景与目标：

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: OBJECTIVE:Cross-sectional studies show that active individuals are leaner than their sedentary counterparts. The purpose of this paper is to determine the extent that this is due to self-selection bias, specifically to initially leaner men and women choosing to exercise longer and more intensely. METHODS:Walking quantity (weekly distance) and intensity (speed) were compared to current body mass index (BMI) (BMI(current)) and BMI at the start of walking (BMI(starting)) in 20,353 women and 5174 men who on average had walked regularly for exercise for 7.2 and 10.6 years, respectively. RESULTS:The relationships of both BMI(current) and BMI(starting) to both distance and intensity were nonlinear (convex). On average, BMI(starting) explained >70% of the association between BMI(current) and intensity, and 40 and 17% of the associations between BMI(current) and distance in women and men, respectively. Although the declines in BMI(current) with distance and intensity were greater among fatter individuals than leaner individuals, the portions attributable to BMI(starting) remained relatively constant regardless of fatness. Thus, self-selection bias accounted for most of the decline in BMI with walking intensity and smaller, albeit significant, proportions of the decline with distance. CONCLUSION:Although walking intensity and walking distance are both strongly associated with greater leanness, intensity is less likely to be causally related to leanness than is distance, and the latter should be encouraged for reversing or preventing weight gain.

背景与目标：

BACKGROUND & AIMS: :Male breast cancer (MBC) is an uncommon neoplasm that shares several biologic characteristics with its female counterpart. In the latter, abnormalities in the expression and/or copy number of the ERBB2 gene are present in 10% to 30% of invasive carcinoma and behave as poor prognostic markers. ERBB2 abnormalities have also been reported in MBC, yet at lower frequency, but their prognostic significance remains controversial. Furthermore, no study has addressed the impact of chromosome 17 abnormalities in MBC survival. In this study, the ERBB2-gene status (overexpression and amplification) and chromosome 17 numerical abnormalities were investigated in a series of 50 archival cases of MBC. The results, together with patient's age, histologic grade, pathologic stage, and estrogen receptor status were correlated with overall survival. ERBB2-protein overexpression was present in 7 cases (14%), ERBB2-gene amplification in 4 (8%), and aneuploidy of chromosome 17 in 12 cases (33.3%). The pathologic stage, ERBB2 overexpression and ERBB2 amplification were significantly correlated with overall survival (P=0.002, 0.016, and 0.009, respectively). No correlation was observed between chromosome 17 aneuploidy and overall survival. Therefore, despite their low incidence in MBC, expression abnormalities of ERBB2 behave, together with the pathologic stage of the tumor, as predictors of overall survival, akin to what has been reported for its female counterpart.

背景与目标： : 男性乳腺癌 (MBC) 是一种罕见的肿瘤，与女性具有多种生物学特征。在后者中，ERBB2基因的表达和/或拷贝数的异常存在于10% 浸润性癌的30% 中，并且表现为不良的预后标志物。在MBC中也有ERBB2异常的报道，但频率较低，但其预后意义仍存在争议。此外，还没有研究涉及17号染色体异常对MBC存活的影响。在这项研究中，在一系列50例MBC档案病例中研究了ERBB2-gene状态 (过表达和扩增) 和17号染色体数字异常。结果以及患者的年龄，组织学分级，病理分期和雌激素受体状态与总生存率相关。ERBB2-protein过表达7例 (14%)，ERBB2-gene扩增4例 (8%)，17号染色体非整倍性12例 (33.3%)。病理分期，ERBB2过表达和ERBB2扩增与总生存期显着相关 (分别为P = 0.002，0.016和0.009)。在17号染色体非整倍性与总生存率之间未观察到相关性。因此，尽管ERBB2在MBC中的发生率较低，但其表达异常与肿瘤的病理阶段一起表现为总体生存的预测指标，类似于已报道的女性对应物。

BACKGROUND & AIMS: BACKGROUND:Testosterone replacement in hypogonadal males improves body composition, sexual function, and health-related quality of life. Male cancer survivors are at risk of androgen deficiency; however, when and in whom testosterone should be replaced remain unanswered questions. OBJECTIVE:The aim of our study was to define the prevalence of androgen deficiency in this patient group through assessment of testosterone levels and related measures. DESIGN:This was a cross-sectional, observational study of cases and controls. We recruited 176 cancer survivors and 213 controls, aged 25-45 yr. RESULTS:Of cancer survivors, 97% had received chemotherapy and 40% radiotherapy. Cancer survivors had lower total testosterone (tT) levels than controls (mean difference 2.67 nmol/liter; 95% confidence interval 1.58-3.76; P = 0.003), and 24 of 176 (13.6%; 95% confidence interval 9.3-19.5) had a tT less than 10 nmol/liter, which was less than 2.5% centile for controls. Cancer survivors had a greater fat mass, higher fasting insulin and glucose levels, increased fatigue, and reduced sexual function and health-related quality of life. In both cohorts, the tT correlated negatively with insulin levels and negatively with body fat mass; however, the difference in tT between them was independent of fat mass. We measured tT and SHBG and calculated bioavailable testosterone. The changes in calculated bioavailable testosterone were similar to tT. CONCLUSIONS:A significant proportion of young male cancer survivors had a frankly low tT associated with an increased fat mass and insulin level compared with controls. These factors would be predicted to improve in response to testosterone replacement therapy and provide a powerful argument for an interventional study of testosterone therapy in young male cancer survivors.

背景与目标：

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: :Y-autosomal translocation has been previously reported in association with male infertility; however, the mechanisms of Y-autosomal translocation and non‑obstructive azoospermia or severe oligospermia remain unclear. G‑banding and fluorescence in situ hybridization (FISH) were performed to analyze the translocation of chromosomes, and a single nucleotide polymorphism (SNP) genotyping assay was used to test mutations. The present study describes three new cases with a de novo balanced translocation t(Y;13), t(Y;9) and t(Y;6). To further explore the genotype‑phenotype correlation, G‑banding and FISH were performed and indicated the presence of a derivative chromosome. The SNP genotyping assay using a microarray revealed no abnormality, especially in the Y chromosome. Molecular deletion analysis demonstrated that no microdeletion was detected in the azoospermia factor region of the Y chromosome in the examined, infertile men. Based on these observations, the authors proposed the hypothesis that a position effect involving unknown spermatogenesis regulatory gene(s) serves a key role in male infertility.

背景与目标： : Y常染色体易位与男性不育有关。但是，Y常染色体易位和非阻塞性无精子症或严重少精子症的机制尚不清楚。进行g-带和荧光原位杂交 (FISH) 以分析染色体的易位，并使用单核苷酸多态性 (SNP) 基因分型分析来测试突变。本研究描述了三个从头平衡易位t(Y;13)，t(Y;9) 和t(Y;6) 的新病例。为了进一步探索基因型表型的相关性，进行了g-带和FISH，并指出存在衍生染色体。使用微阵列的SNP基因分型分析未显示异常，尤其是在Y染色体中。分子缺失分析表明，在被检查的不育男性中，在Y染色体的无精子因子区域中未检测到微缺失。基于这些观察结果，作者提出了以下假设: 涉及未知精子发生调节基因的位置效应在男性不育中起关键作用。