新型有机锗化合物的合成、抗癌活性及其与DNA的相互作用研究

有机锗化合物具有广谱抗癌活性和低毒副作用，有关它们的合成、生物活性及应用研究引起了医药界和化学界的兴趣。但由于未注重有机基团的相关性，忽略了分子整体对抗癌作用的影响，至今尚未出现临床应用的高效低毒的有机绪抗癌新药，分子结构与抗癌活性关系及抗癌作用机理仍不清楚。因此，继续合成新型且具有结构可比性的有机锗抗癌活性化合物，研究药物与生物大分子DNA的相互作用、揭示有机锗化合物的结构与抗癌作用关系，具有重要的理论意义和应用价值。为此，本论文就以下几个方面开展了研究工作。1、合成了4种有机锗二元杂环化合物一有机锗喳琳醋和有机锗蔡酚醋化合物。根据它们的光谱性质讨论了其结构特征，该类化合物具有与Ge-132类似的空间结构，即具有-Ge-O-Ge-O-聚合网络大环结构。由于保留了有机锗倍半氧化物的基本结构，同时引入了能够与DNA有强烈相互作用的蔡酚和喳琳基团，可能会产生协同效应，使新化合物具有较强的抗癌活性和较好的选择性。2、在保留有机锗倍半氧化物的基本结构的基础上，引入了本身具有抗癌活性和光谱学性质，并且能够与DNA有相互作用的葱、葱醒、菲、荀、荀酮等三环有机基团，合成了16种未见报道的有机锗三元杂环化合物。以葱环为代表的杂环化合物，例如氮杂葱醌及氮杂葱并吡唑类化合物，作为重要的抗癌活性化合物，引起了药学界的极大兴趣。我们合成的新化合物，既保留了有机锗倍半氧化物的基本结构，又引入了葱环类化合物，进而使新化合物具有较强的抗癌活性和选择识别性。3、选择了8个药物小分子，分别应用UV-Vis、热变性（Melting）、荧光光I新型有机锗化合物的合成、抗癌活性及其与DNA的相互作用研究谱变化、粘度测定等方法，研究它们与3种DNA，即小牛胸腺DNA（CT－DNA）和2种人I合成的寡聚核昔酸［22一merspoly（dA·d劝和22一merspoly（dG·dC）］的相互作用。发现与DNA作用后，这些化合物的紫外吸收光谱均发生减色效应和红移现象，它们能使3种DNA的热变性温度（几）升高，粘度增加，说明化合物是以插入方式与DNA结合的。应用荧光滴定方法，求得了新化合物与DNA的结合常数，场在1护一105M一l范围内，属中等强度结合。进一步研究发现它们是以1：2（小分子／碱基对）的计量比与DNA碱基结合的。4、2种有机锗菲醋化合物（G一1、G一2）与DNA结合后，紫外吸收光谱产生减色效应和兰移现象以及荧光淬灭，对DNA的粘度基本无影响，它们是以沟槽结合方式与DNA发生作用的。发现G-1和G-2不仅能够增加三链DNA-Polv（dA·ZdT油的稳定性，并且能够促进Poly（dA．ZdT）22的形成。这一结果说明，某些结构的有机锗化合物可能以这种作用机理发挥抗癌作用，同时可以作为潜在的三链DNA稳定剂。5、研究了部分新合成的有机锗化合物（GK－1，GK-2，GN-1，GN-2，EK-1，EK-2，D-1，D-2，G-，G-2）对PC一3M和K562癌细胞的作用。GK-1，GK-2能够显著抑"制PC一3M细胞的增值，而且对细胞形态也产生了严重影响，显示了明显的细胞毒作用。流式细胞实验结果表明EK类化合物对PC-3M细胞周期有很大影响，发现对细胞增值的抑制作用发生在S期，即细胞内DNA合成期，细胞实验的结果也进一步验证了药物与DNA相互作用的事实。GN-1，GN-2，EK-1，EK-2，D-1，D-2，G-和G一2对K562细胞表现了较强的抑制作用，尤其GN-1和GN-2，效果更为明显，说明分子内有机锗链和其它基团的协向作用增强了整体化合物的生物学作用。6、有机锗二元杂环化合物与DNA的结合常数和体外抗癌活性明显高于有机锗三元杂环化合物，结合强度和抗癌活性之间呈现线形相关性。有机链中甲基的存在不利于有机锗二元杂环化合物与DNA的作用，同时降低了抗癌活性，而同样甲基的存在有利于有机锗三元杂环化合物与DNA的相互作用和抗癌功能的发挥。

Interactions of thiamine monophosphate (TMP) with one- and two-dimensional polymeric halogenomercurate anions. Crystal structures of (TMP)(Hg2Br5)center dot 0.5H(2)O and (TMP)(2)(Hg3I8)

An investigation into the interactions between thiamine monophosphate (TMP) and anions has resulted in the preparation and X-ray characterization of the compounds (TMP)(Hg2Br5).0.5H(2)O (1) and (TMP)(2)(Hg3I8) (2). In each compound the TMP molecule exists as a monovalent cation in the usual F conformation. The halogenomercurate anions occur in two-dimensional (2-D) network in 1 or one-dimensional (1-D) chain in 2. In both 1 and 2, the structures consist of alternating cationic sheets of the hydrogen-bonded TMP molecules and anionic sheets of the polymeric halogenomercurate anions. The TMP molecule binds to the polymeric anions through the characteristic 'anion bridge I', C(2)-H..X...pyrimidinium (X = Br in 1 and 1 in 2), and electrostatic interactions between electropositive S(1) and halogen atoms. The 'anion bridge II' of the type N(4'1)-H...X...thiazolium (X = phosphate group) plays a role in stabilizing the molecular conformation. The biological implication of the host-guest-like complexation between TMP and polymeric anions is discussed.

Metal ion and anion coordination in the thiamine-[Pt-II(NO2)(4)](2-) system. Structures of a metal complex, Pt(thiamine)(NO2)(3), and two salts, (H-thiamine)[Pt(NO2)(4)]center dot 2H(2)O and (thiamine monophosphate)(2)[Pt(NO2)(4)]center dot 2H(2)O

Reaction of thiamine or thiamine monophosphate (TMP) with K2Pt(NO2)(4) afforded a metal complex, Pt(thiamine)(NO2)(3) (1), and two salt-type compounds, (H-thiamine)[Pt(NO2)(4)]. 2H(2)O (2) and (TMP)(2)[Pt(NO2)(4)]. 2H(2)O (3), which were structurally characterized by X-ray diffraction. In 1, the square-planar Pt2+ ion is coordinated to the pyrimidine N(1'), a usual metal-binding site, and three NO2- groups. The thiamine molecule exists as a monovalent cation in 1 and a divalent cation in 2 while the TMP molecule is a monovalent cation in 3. In each compound, thiamine or TMP adopts the usual F conformation and forms two types of host-guest-like interactions with anions, which are of the bridging forms, C(2)-H . . . anion . . . pyrimidine-ring and N(4'1)-H(...)anion(...)thiazolium-ring. In 3, there is an additional anion-bridging interaction between the pyrimidine and thiazolium rings of TMP, being of the form C(6')-H . . . anion . . . thiazolium-ring. The salts 2 and 3 show similar hydrogen-bonded cyclic dimers of thiamine or TMP between which the anions are held. Results are compared with those of the other thiamine-platinum complexes. (C) 2001 Elsevier Science B.V. All rights reserved.

Host-guest-like thiamine-anion complexation in thiaminium bis(tetrafluoroborate)

In the title compound, 3-[(4-amino-2-methyl-5-pyrimidin-1-io)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium(2+) bis(tetrafluoroborate), C12H18N4OS2+. 2BF(4)(-), the divalent thiamine cation (in the F conformation) is associated with BF4- anions via two characteristic bridging interactions between the thiazolium and pyrimidinium rings, i.e. C-H . . . BF4- . . . pyrimidinium and N-H . . . BF4- . . . thiazolium interactions. Thiamine molecules are linked by N-H . . .O hydrogen bonds to form a helical chain structure.

FACTOR-ANALYSIS SPECTROPHOTOMETRY FOR THE SIMULTANEOUS DETERMINATION OF VALENCE STATES OF METALS

Two M(n+)-2-(5-bromo-2-pyridylazo)-5-diethylaminophenol systems for the simultaneous determination of the valence states of Cr and Fe using factor analysis were studied. (1) At pH 4.0, Cr(III) and Cr(VI) react with the reagent to form stable complexes and a slight difference in the wavelengths of maximum absorption (lambda(max.)) between the two complexes is observed when the sodium lauryl sulfate, which also acts as a solubilizing and sensitizing agent, is added, viz., 590 nm for Cr(III) and 593 nm for Cr(VI) complexes. (2) In the presence of ethanol, both Fe(II) and Fe(III) form 1:2 complexes with the reagent at pH 2.5-3.5 and the lambda(max.) of the Fe(II) and Fe(III) complexes is at 557 and 592 nm, respectively. In the target transformation factor analysis, the K coefficients calculated from the standard mixtures by classical least-squares analysis and a non-zero intercept added to each wavelength are used as the target vector instead of the pure component standards; this can decrease the analysis errors introduced by the interaction between the two species and by deviations from Beer's law.

Trójpłaszczyznowa Szachownica. Segmentacja „Wielkiej Polityki” w rozważaniach Josepha Nye’a

Autor książki: Wielka szachownica. Cele polityki amerykańskiej (Warszawa 1998) postrzega stosunki wzajemne pośród uczestników areny międzynarodowej jako wielką szachownicę, na której toczy się pomiędzy nimi „Wielka Polityka” (gra). Sytuacja światowa rozgrywa się, według niego, na jednej szachownicy (arenie międzynarodowej), a uczestnicy „gry” zajmują pozycje pionków. Jest to, więc swoista partia szachów, gdzie silniejszy zdobywa prestiż, pieniądze i władzę, natomiast słabszy przegrywa wszystko, osiągając marginalne znaczenie na globalnej szachownicy. Z kolei J. Nye eksponuje trzy płaszczyzny tej samej szachownicy, a mianowicie: potęgę militarną, gospodarczą oraz „miękkie środki oddziaływania politycznego”, wokół których toczy się polityka międzynarodowa. Jego trylogia poświęcona postrzeganiu potęgi państw powinna być lekturą obowiązkową, skierowaną przede wszystkim do polityków i mężów stanu, z przesłaniem, aby wskazane przez autora czynniki siły stosowali w praktyce, co pomoże im lepiej władać państwem. Jest to także książka przeznaczona dla wszystkich zainteresowanych polityką i jej zagadnieniami związanymi z percepcją potęgi. W niniejszej rozprawie naukowej skoncentrowałam się na trzech najważniejszych książkach J. Nye’a, stanowiących analizę atrybutów potęgi i wyjaśniających jej znaczenie. Są to: Bound to Lead. The Changing Nature of American Power (New York 1991), The Paradox of American Power. Why the World’s Only Superpower Can’t Go It Alone (Oxford 2002) oraz Soft Power. The Means to Success in World Politics (New York 2004; wyd. polskie: Soft Power. Jak osiągnąć sukces w polityce światowej, Warszawa 2007). Stanowią one podstawę do zrozumienia percepcji pojęcia potęgi Stanów Zjednoczonych. Choć autora zajmują także kwestie innych państw, to jednak właśnie mocarstwowość USA jako najpotężniejszego kraju na świecie, posiadającego wszelkie czynniki wzmacniające jego potęgę (władzę), stanowi podstawę rozważań J. Nye’a.

Wykładnia funkcjonalna a zmiana społeczno-polityczna. Studium teoretycznoprawne

Wydział Prawa i Administracji: Katedra Teorii i Filozofii Prawa

Uczenie działań komunikacyjnych poprzez bezpośrednią instrukcję

The article focuses on teaching and learning conversational actions in English as a FL in direct instruction based on the guided discovery observation of discourse models such as transcribed video discus-sions and conversations. The aim of the task is to develop students’ communicative awareness, which in turn allows them to find in dis-course those communicative actions which suit their communicative style and contribute to the development of their personal communicative competence. Discourse observation tasks are accompanied by project tasks such as classroom role plays and discussions and interviews with a foreigner in which students are expected to produce the observed communicative actions. The paper is based on a case study of one student’s performance in the selected two types of tasks, discourse observation tasks and an interview with a foreigner.

Uczenie działań komunikacyjnych poprzez bezpośrednią instrukcję

The article focuses on teaching and learning conversational actions in English as a FL in direct instruction based on the guided discovery observation of discourse models such as transcribed video discus- sions and conversations. The aim of the task is to develop students’ communicative awareness, which in turn allows them to find in dis- course those communicative actions which suit their communicative style and contribute to the development of their personal communic- ative competence. Discourse observation tasks are accompanied by project tasks such as classroom role plays and discussions and inter- views with a foreigner in which students are expected to produce the observed communicative actions. The paper is based on a case study of one student’s performance in the selected two types of tasks, dis- course observation tasks and an interview with a foreigner.

Auriculotherapy for pain management: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Side-effects of standard pain medications can limit their use. Therefore, nonpharmacologic pain relief techniques such as auriculotherapy may play an important role in pain management. Our aim was to conduct a systematic review and meta-analysis of studies evaluating auriculotherapy for pain management. DESIGN: MEDLINE,(®) ISI Web of Science, CINAHL, AMED, and Cochrane Library were searched through December 2008. Randomized trials comparing auriculotherapy to sham, placebo, or standard-of-care control were included that measured outcomes of pain or medication use and were published in English. Two (2) reviewers independently assessed trial eligibility, quality, and abstracted data to a standardized form. Standardized mean differences (SMD) were calculated for studies using a pain score or analgesic requirement as a primary outcome. RESULTS: Seventeen (17) studies met inclusion criteria (8 perioperative, 4 acute, and 5 chronic pain). Auriculotherapy was superior to controls for studies evaluating pain intensity (SMD, 1.56 [95% confidence interval (CI): 0.85, 2.26]; 8 studies). For perioperative pain, auriculotherapy reduced analgesic use (SMD, 0.54 [95% CI: 0.30, 0.77]; 5 studies). For acute pain and chronic pain, auriculotherapy reduced pain intensity (SMD for acute pain, 1.35 [95% CI: 0.08, 2.64], 2 studies; SMD for chronic pain, 1.84 [95% CI: 0.60, 3.07], 5 studies). Removal of poor quality studies did not alter the conclusions. Significant heterogeneity existed among studies of acute and chronic pain, but not perioperative pain. CONCLUSIONS: Auriculotherapy may be effective for the treatment of a variety of types of pain, especially postoperative pain. However, a more accurate estimate of the effect will require further large, well-designed trials.

Unrecognized pretransplant and donor‐derived cryptococcal disease in organ transplant recipients.

BACKGROUND: Cryptococcosis occurring ≤30 days after transplantation is an unusual event, and its characteristics are not known. METHODS: Patients included 175 solid-organ transplant (SOT) recipients with cryptococcosis in a multicenter cohort. Very early-onset and late-onset cryptococcosis were defined as disease occurring ≤30 days or >30 days after transplantation, respectively. RESULTS: Very early-onset disease developed in 9 (5%) of the 175 patients at a mean of 5.7 days after transplantation. Overall, 55.6% (5 of 9) of the patients with very early-onset disease versus 25.9% (43 of 166) of the patients with late-onset disease were liver transplant recipients (P = .05). Very early cases were more likely to present with disease at unusual locations, including transplanted allograft and surgical fossa/site infections (55.6% vs 7.2%; P < .001). Two very early cases with onset on day 1 after transplantation (in a liver transplant recipient with Cryptococcus isolated from the lung and a heart transplant recipient with fungemia) likely were the result of undetected pretransplant disease. An additional 5 cases involving the allograft or surgical sites were likely the result of donor‐acquired infection. CONCLUSIONS: A subset of SOT recipients with cryptococcosis present very early after transplantation with disease that appears to occur preferentially in liver transplant recipients and involves unusual sites, such as the transplanted organ or the surgical site. These patients may have unrecognized pretransplant or donor-derived cryptococcosis.

Pulsating tandem microbubble for localized and directional single-cell membrane poration.

The interaction of laser-generated tandem microbubble (maximum diameter of about 50  μm) with single (rat mammary carcinoma) cells is investigated in a 25-μm liquid layer. Antiphase and coupled oscillation of the tandem microbubble leads to the formation of alternating, directional microjets (with max microstreaming velocity of 10  m/s) and vortices (max vorticity of 350 000  s{-1}) in opposite directions. Localized and directional membrane poration (200 nm to 2  μm in pore size) can be produced by the tandem microbubble in an orientation and proximity-dependent manner, which is absent from a single oscillating microbubble of comparable size and at the same stand-off distance.