published_or_final_version / abstract / Chemistry / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

published_or_final_version / abstract / Surgery / Master / Master of Philosophy

published_or_final_version / abstract / Chinese Medicine / Master / Master of Philosophy

published_or_final_version / Surgery / Master / Master of Philosophy

A series of novel Bis 2,2':6',2″-terpyridinyl ligands, linked through a flexible alkyl chain situated at the 4' position, were synthesised and characterised by microanalysis, FTIR, NMR, UV-Visible spectroscopy, and MS-ToF. Single crystals of all the ligands were obtained, of which one has been published, one has been submitted for publication and one is in preparation for publication. These ligands were then coordinated to platinum(II) and characterised, including ¹⁹⁵Pt NMR spectroscopy. A detailed kinetic study involving the substituting the chloride co-ligand with the following nucleophiles thiourea, 1,3-dimethyl-thiourea and 1,1,3,3-tetramethyl-thiourea was conducted using stopped-flow techniques. An associative reaction mechanism was suggested for the pendant ligand substitution and the following trend in reactivity was observed: L2-Ptα > L3-Ptβ > L1-Ptχ. UV-Visible absorption spectra were recorded on sequentially diluted solutions of the ligands (in chloroform), and the platinum complexes (in water). These spectra obeyed the Beer-Lambert law. The values of the molar absorption coefficients at the wavelengths of maximum absorption for the ligands followed the trend L1 < L2 < L3, whilst for the complexes the trend was L1-Pt < L3-Pt < L2-Pt. It has been concluded that at low concentrations L2-Pt and L3-Pt undergo intramolecular folding. Variable temperature and variable concentration NMR spectroscopic studies were performed on all three complexes. At higher complex concentrations intermolecular self-association takes place for L2-Pt and L3-Pt but not for L1-Pt. The reactivity of the complexes is predominately determined by their structural conformations in solution. At low concentrations the L1-Pt complex remains in its linear conformational state, whilst the L2-Pt and L3-Pt complexes undergo intramolecular folding with the formation of an axial Pt—Pt bonded and π—π stacked dinuclear platinum terpyridine centre. The latter is believed to be more active in the substitution reaction than the original mononuclear centre. The reasons for the folding and self-association in the L2-Pt and L3-Pt systems are related to the steric crowding and stress in the spacer region of the folded or self-associated complexes. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2012.

The effects of three oral dosages (0.4 mg, 0.8 mg, and 1.6 mg) of quercetin on Colon-25 tumors implanted in Balb-c mice were studied. The data in this study show that: (1) certain dosages of quercetin in alcohol solutions, reduces the weight, and size of implanted Colon-25 tumors in Balb-c mice, (2) these same dosages of quercetin all produce a profound neutrophilia combined with a significant lymphopenia at day 20 post-implantation, and (3) there was relatively little evidence of histological changes in the quercetin-treated tumor section which would indicate that the action(s) of quercetin is primarily at the subcellular level probably within the nuclei of the tumor cells.

多年來，儘可能多的從植物中提取單體化合物一直是開發新型化學防癌劑和化學治療劑藥物的重要來源。 / 在本课题中，我们活性測試了从刺果紫玉盘（番荔枝科植物）中分离得到的14个番荔枝内酯化合物和7个多氧环己烯化合物，从三叉刺（豆科植物）和黄瑞香（瑞香科植物）中分离得到的4个黄酮化合物，从黄瑞香（瑞香科植物）和了哥王（瑞香科植物）中分离得到的2个香豆素化合物，以及从总状蕨藻（蕨藻科植物）中分离得到的1 个生物碱化合物，對11種人類常見癌症細胞株，如惡性黑色素瘤、肺癌、子宮頸上皮腺癌、肝癌、前列腺癌、結直腸癌的體外抗癌活性，用以建立一個全面的抗癌活性數據庫，為人們更好得了解番荔枝科植物奠定基礎。 / 在這些被篩選的單體化合物中，番荔枝內酯（ACGs）顯示出卓越的抗癌活性。它們對某些癌細胞株的細胞毒性甚至達到了nmol/l級別。例如番荔枝內酯desacetyluvaricin（Dau），對11條人類癌細胞株具有廣泛的抗增生活性，其半抑制濃度（IC₅₀）範圍從2.3 nM到37.4 μM。其中，Dau對結直腸癌細胞SW480的毒性最甚。Dau不僅具有高的抗癌效力，并對人正常纖維細胞Hs68幾乎沒有細胞毒性，半抑制濃度超過了247.5 μM。進一步的機理研究表明，Dau可導致SW480細胞產生大量過氧化物，進而導致細胞核內DNA斷裂。DNA損傷會讓MEK/ERK信號通路失活，並且影響了細胞週期調控蛋白的正常表達。例如影響細胞S週期的調控蛋白Cyclin A和Cyclin E的表達，以及影響G₁/S檢查點調控蛋白E2F的表達。由此，Dau促進SW480癌細胞穿過G₁/S檢查點，由G₁進入S期並在S期累計。最終被抑制在S週期的SW480細胞發生了壞死。以上機理的研究可為更好的理解ACG的作用機制提供一定的理論基礎。 / 番荔枝內酯是一系列長鏈脂肪酸的衍生物。它的結構的多樣性引發了我們極大的興趣去研究它的構效關係。我們比較了14個番荔枝內酯在細胞毒性和細胞週期控制方面對兩種不同的前列腺癌細胞LNCaP（p53基因野生型）和PC-3（p53基因缺失型）的影響。實驗結果表明，LNCaP細胞比PC-3更加敏感。番荔枝內酯的這種選擇性大概跟癌細胞中p53抑癌蛋白的表達水平有關。此外，關於構效關係的研究我們還發現：（1）在番荔枝內酯結構的核心系統中，四氫呋喃環的個數越多，化合物的抗癌活性越高；（2）在含有相鄰雙四氫呋喃環結構的化合物中，擁有threo/trans/threo/trans/erythro立體構型的化合物的細胞毒性比擁有threo/trans/threo/trans/threo立體構型的化合物高；（3）含單或雙四氫呋喃環結構的番荔枝內酯都將通過將LNCaP細胞抑制在G₁/G₀週期從而達到抗癌效果，並不會引起細胞凋亡；（4）含單四氫呋喃環結構的番荔枝內酯都將通過引發細胞凋亡從而達到抑制PC-3癌細胞的增長。然而含雙四氫呋喃環結構的番荔枝內酯會引發更多的PC-3細胞凋亡，並且有不同程度的細胞週期抑制；（5）在四氫呋喃環核心體系上，乙酰氧基會比羥基增加番荔枝內酯的細胞毒性；（6）雙鍵的取代基也會增加毒性效果。我們的研究結果印證了一些文獻已報導的關於番荔枝內酯構效關係的結論，同時我們也提出了一些新的假設。 / 本研究不僅增加了我們對番荔枝內酯強大的抗癌活性更全面的了解，並且通過機理研究還為它的選擇性毒性及構效關係特點提供了有重要的信息。番荔枝內酯是一類具有充滿前景抗癌化合物。在接下來的研究中，我們將致力於體內抗癌活性的研究，并擴大研究範圍，通過對多個ACG化合物的機理研究來證明我們對它的選擇性毒性的機理假設。 / For years and years, the discovery of phytochemicals as many as possible has always been an important strategy for the development of novel chemopreventive and chemotherapeutic drugs. / In this studies, we have screened 14 Annonaceous acetogenins and 7 polyoxygenated cyclohexenes isolated from the root of Uvaria calamistrata (Annonaceae), 4 flavonoids isolated from the stems of Trifidacanthus unifoliolatus (Fabaceae) and Daphne giraldii (Thymelaeaceae), 2 cumarins isolated from the stem bark of Daphne giraldii (Thymelaeaceae) and the root of Wikstroemia indica (Thymelaeaceae), and 1 alkaloid isolated from Caulerpa racemosa (Caulerpaceae). The in vitro anticancer effects of these 28 natural compounds on 11 human cancer cell lines, including malignant melanoma, lung carcinoma, cervix epithelial adenocarcinoma, liver carcinoma, prostate adenocarcinoma and colorectal adenocarcinoma, were tested to set up an overall anticancer activity database for better understanding of the biological actions of Annonaceous plants. / Among the screened natural compounds, Annonaceous acetogenins (ACGs) exhibited outstanding anticancer efficacy. The cytotoxicities of ACGs to some cancer cell lines were even at nmol/l level. For instance, desacetyluvaricin (Dau), an ACG, was identified as a novel antiproliferative agent with a broad spectrum of inhibitions against the tested 11 human cancer cell lines with the IC₅₀ values ranging from 2.3 nM to 37.4 μM, and was especially cytotoxic to SW480 human colorectal carcinoma cells. Despite this potency, Dau was virtually nontoxic toward Hs68 human fibroblasts with an IC₅₀ value exceeding 247.5 μM. Further cell death mechanism studies showed that Dau could induce large amounts of superoxide production, which subsequently induced nuclear DNA fragmentation. DNA damage may inactivate the MEK/ERK signaling pathway and disturbed the expressions of cell cycle regulators such as Cyclin A and Cyclin E, which are S phase regulators, and E2F which is the G1/S checkpoint regulator. Thereafter, Dau arrested SW480 cells in S phase by promoting SW480 cells passing through the G₁/S boundary, and then accumulating in S phase. Finally, the SW480 cells underwent necrotic cell death. This mechanism study may provide a better understanding on the action mode of ACGs. / ACGs are derivatives of long chain fatty acids. Its structural diversity kindled our great interests in its structure-activity relationship (SAR). Therefore, we compared the cytotoxicities and cell cycle regulations of the 14 ACG compounds on two different human prostate cancer cell lines, LNCaP (p53 wild-type) and PC-3 (p53 null-type). Results showed that LNCaP cells were more sensitive to ACGs than PC-3 cells. This selectivity may be due to the presence of p53 tumor suppressor gene. Moreover, we found about SAR study that (1) the more THF rings existing in the core structure of ACGs, the more potent anticancer effects of ACGs would be; (2) for the adjacent bis-THF ACGs, stereo-structure with threo/trans/threo/trans/erythro configuration is generally more cytotoxic than the one with threo/trans/threo/trans/threo configuration; (3) both mono-THF ACGs and bis-THF ACGs inhibited LNCaP cells growth by G₁/G₀ phase arrest without any apoptosis induction; (4) mono-THF ACGs inhibited PC-3 cells growth by inducing apoptosis without cell cycle disturbance. However, the bis-THF ACGs could induce more apoptosis in PC-3 cells with partially cell cycle arrest. (5) the -OAc substituent group instead of -OH in the THF system would enhance the cytotoxicity efficacies of ACGs; (6) the double bond substituent would also enhance the anticancer effect. Our studies have proved several reported disciplines about the SAR of ACGs, and also proposed some new hypothesis. / Taken together, this study not only increased our understanding on the potent anticancer effects of ACG, but also provided valuable information on explaining its special cytotoxicities and the SAR properties through underling mechanism study. ACGs are a group of promising anticancer compounds with potent and steady activities. In the future work, we should further examine the in vivo anticancer effects and study more ACGs on their action modes to validate our hypothesis on their sensitivities to certain cancer cell lines. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Xue, Junyi. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 215-236). / Abstracts also in Chinese.

Orientador: Áureo Evangelista Santana / Coorientadora: Annelise Carla Camplesi / Banca: Marco Antônio de Andrade Belo / Banca: Thiago Demarchi Munhoz / Resumo: A quimioterapia metronômica é uma estratégia de uso crescente em Medicina Veterinária, que emprega fármacos em baixas doses e por longos períodos de tempo para controlar o crescimento tumoral. Objetivou-se avaliar os efeitos tóxicos de dois quimioterápicos antineoplásicos em animais livres de tumores seguindo esquemas metronômicos, assim como os efeitos residuais uma vez que a terapia foi suspensa. Para tanto, foram empregados 54 ratos Wistar, divididos em 3 grupos de tratamento de 18 animais cada, que receberam doses baixas de ciclofosfamida (CPX), metotrexato (MTX) ou placebo (grupo controle, CTR), via oral, por meio de gavage, durante 45 dias. Os animais tiveram acompanhamento periódico para pesagem e monitoramento clínico e do consumo de alimento e água. Realizou-se eutanásia em seis animais de cada grupo aos 30 (M1), 45 (M2) e 60 dias (M3), para coleta de amostras para hemograma, bioquímica sérica, citologia de medula óssea e análise histopatológica de baço, fígado, rim, intestino, pulmão, coração, cérebro e artéria. Empregou-se o teste de Qui-quadrado para análise estatística das variáveis não paramêtricas e o teste T-student para amostras não pareadas ou uma ANOVA seguida de uma comparação múltipla de Tukey para as variáveis paramêtricas. Seis animais do grupo CPX morreram, portanto a terapia foi suspensa aos 30 dias de tratamento, mantendo o período de observação até 45 dias. Os animais tratados com CPX exibiram significativa redução de peso e do consumo de alimento e... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Metronomic chemotherapy is a growing strategy in veterinary medicine that uses low doses of antineoplastic drugs for sustained periods of time to control tumor growth. This work aimed to evaluate toxic effects of metronomic chemotherapy schemes in tumor-free animals, and residual toxicity once treatment was suspended. There were used 54 healthy Wistar rats, divided in 3 groups (18 animals each), that received low-doses of cyclophosphamide (CPX), methotrexate (MTX) or placebo (control group, CTR) by oral gavage during 45 days. Clinical alterations, body weight, water and food intake were monitored periodically. Euthanasia was practiced within 6 animals from each group at 30 (M1), 45 (M2) and 60 days (M3) to perform hematological, biochemical and histopathologic analysis (spleen, liver, kidney, gut, lung, heart, brain and artery), and bone marrow cytology. An unpaired T-student test or a one-way ANOVA in conjunction with a Tukey multiple comparison test were done to analyze parametrical data, as a Chi-square test for semi-quantitative parameters. Six animals treated with CPX died and therapy was suspended at 30 days, within 15 days of observation after withdrawal. CPX treated animals exhibited significant reduction of weight gain, water and food intake (p<0.05), and clinical alterations related to respiratory and neuromuscular involvement, which even persisted after CPX withdrawal. At M1, significant neutrophil augmentation and reduction of leukocytes, lymphocytes and albumin was predominant in blood, as bone marrow reduction of lymphocytes, plasmatic cells and mature erythroid populations were significantly prevalent (p<0.05). At M2, only higher neutrophils count and reduction of lymphocytes persisted, as depletion of mature erythroid populations (p<0.05). MTX treated animals only evidenced mild to moderate (Complete abstract click electronic access below) / Mestre