329 research outputs found
Folate receptor targeted PDT in lung cancer
No full textObjective: Despite modest improvements, the prognosis of lung cancer patients has still remained poor and new treatment are urgently needed. Photodynamic therapy (PDT), the use of light-activated compounds (photosensitizers) is a treatment option but its use has been restricted to central airway lesions. Here, we report the use of novel porphyrin-lipid nanoparticles (porphysomes) targeted to folate receptor 1 (FOLR1) to enhance the efficacy and specificity of PDT that may translate into a minimally-invasive intervention for peripheral lung cancer and metastatic lymph nodes of advanced lung cancer. Materials and methods: The frequency of FOLR1 expression in primary lung cancer and metastatic lymph nodes was first analyzed by human tissue samples from surgery and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA). Confocal fluorescence microscopy was then used to confirm the cellular uptake and fluorescence activation in lung cancer cells, and the photocytotoxicity was evaluated using a cell viability assay. In vivo fluorescence activation and quantification of uptake were investigated in mouse lung orthotopic tumor models, followed by the evaluation of in vivo PDT efficacy. Results: FOLR1 was highly expressed in metastatic lymph node samples from patients with advanced lung cancer and was mainly expressed in lung adenocarcinomas in primary lung cancer. Expression of FOLR1 in lung cancer cell lines corresponded with the intracellular uptake of folate-porphysomes in vitro. When irradiated with a 671 nm laser at a dose of 10 J/cm2, folate-porphysomes showed marked therapeutic efficacy compared with untargeted porphysomes (28% vs. 83% and 24% vs. 99% cell viability in A549 and SBC5 lung cancer cells, respectively). Systemically-administered folate-porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast. Folate-porphysomes mediated PDT successfully inhibited tumor cell proliferation and activated tumor cell apoptosis. Conclusion: Folate-porphysome based PDT shows promise in selectively ablating lung cancer based on FOLR1 expression in these preclinical models
PDT efficacy against resistant melanoma cells
No full textFunding Information:
Thanks are also due to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP- 2016/12707-0 and 2019/19448-8) and Universidade de São Paulo. K.A.D.F. Castro also thanks CAPES for her post-doctoral fellowships (PNPD/CAPES). NMM Moura thanks FCT for his contract (Ref: CDL-CTTRI-048-88-ARH/2018). We also thank Dr. Maurício da Silva Baptista (Cepid Redoxoma 2013/07937-8) from the Institute of Chemistry, University of São Paulo, for his laboratory and equipment support and Dr. Helena Couto Junqueira for technical assistance. C.L thanks to the PROTEOMASS Scientific Society (Portugal) (General Funding Grants 2018–2019).
Publisher Copyright:
© 2022 Elsevier LtdPorphyrin derivatives present an excellent ability to act as photosensitizers (PS) in photodynamic therapy (PDT). Ruthenium and iridium complexes, mainly containing pyridine ligands, also have been highlighted as potential PS for PDT, due to their photochemical and photophysical properties. The combination of porphyrin derivatives with iridium or ruthenium ions may create singular features and, consequently, improve the PDT effect. In this paper, we report the synthesis, characterization and efficacy of porphyrin derivatives bearing attached ruthenium or iridium terpyridine units to act as PS against resistant melanoma cells (B16F10 cell model). The choice of the porphyrin derivatives to carry out this study was related with their efficacy to generate reactive oxygen species (ROS), the presence of anchoring groups to enable the coordination with ruthenium and iridium metal ions and on the studies of subcellular localization. In the PDT studies, a cell viability decrease was observed in the presence of compounds 4a (ruthenium derivative) and 3b (iridium derivative) at lower concentrations due to the high values of singlet oxygen quantum yield and cellular uptake found. The fluorescence of derivative 3b was observed uniformly dispersed by the cells.authorsversionpublishe
Influence of photodynamic therapy on the adhesive bonding of fiberglass posts inside the root canal
No full textObjetivo: Avaliar a influência do tipo de agente fotossensibilizador e o número de sessões realizadas na terapia fotodinâmica (PDT) quanto à resistência de união adesiva de pinos de fibra de vidro cimentados no canal radicular. Método: Cinquenta incisivos decíduos bovinos foram divididos aleatoriamente em cinco grupos experimentais, de acordo com o tipo de agente fotossensibilizador e o número de sessões realizadas na PDT: GC - sem PDT (controle); GF1M - PDT (1 sessão) com azul de metileno; GF2M - PDT (2 sessões) com azul de metileno; GF1T - PDT (1 sessão) com azul de toluidina; GF2T - PDT (2 sessões) com azul de toluidina. Pinos de fibra de vidro Exacto® foram cimentados com RelyX U200® dentro do canal radicular, permanecendo 15 dias em água destilada. Os corpos de prova foram seccionados com média de 1.56 mm de espessura em cada um dos terços radiculares (cervical, médio e apical) e submetidos ao teste de push-out. Após a realização do teste, as amostras fraturadas foram analisadas em estereomicroscópio para determinação do padrão de fratura. Os dados obtidos foram tratados pelo teste one-way ANOVA (α = 0.05). Resultados: Não houve diferença estatística comparando os tratamentos propostos e os terços radiculares analisados (P>0.05). Conclusão: O tipo de agente fotossensibilizador utilizado e o número de sessões realizadas na PDT não influencia na resistência de união adesiva de pinos de fibra de vidro cimentados intrarradicular.Aim: The aim of this study was to evaluate the influence of the type of photosensitizing agent and the number of photodynamic therapy (PDT) sessions on the resistance of cemented fiberglass posts to displacement within the root canal. Methodology: Fifty bovine primary incisors were randomly divided into five experimental groups according to the type of photosensitizing agent and to the number of PDT sessions: CG - without PDT (control); GF1M - one PDT session with methylene blue; GF2M - two PDT sessions with methylene blue; GF1T - one PDT session with toluidine blue; and GF2T - two PDT sessions with toluidine blue. Exacto® fiberglass posts were cemented with RelyX U200® in the root canal and kept for 15 days in distilled water. The specimens were sectioned with an average thickness of 1.56 mm at the cervical, middle, and apical root thirds and subjected to the push-out test. After the test, the fractured specimens were analyzed under a stereomicroscope to determine the fracture pattern. The data obtained were treated by one-way ANOVA (α = 0.05). Results: There was no statistical difference in the comparison of the proposed treatments and the analyzed root thirds (P> 0.05). Conclusions: The type of photosensitizing agent used and the number of PDT sessions do not influence the resistance of cemented intraradicular fiberglass posts to displacement
INSIGHTS INTO PHOTODYNAMIC THERAPY AND ITS DOSIMETRY USING A DYNAMIC MODEL FOR ALA-PDT OF NORMAL HUMAN SKIN
No full textPhotodynamic therapy (PDT) is a rapidly developing clinical treatment modality involving a light-activatable photosensitizer, tissue oxygen and light of an appropriate wavelength to generate cytotoxic reactive molecular species - primarily singlet oxygen (1O2). Singlet oxygen readily reacts with surrounding biomolecules leading to different biological effects and subsequent therapeutic outcomes. Over the last decades, many standard PDT treatments have been approved worldwide to treat different medical conditions ranging from a variety of cancer conditions to age-related macular degeneration (AMD). Meanwhile, many active clinical trials and pre-clinical studies are underway for other clinical indications. The therapeutic outcomes of PDT are difficult to predict reliably even with many years of research. The fundamental cause for this is the inherent complexity of PDT mechanisms. As PDT involves three main components, the outcomes of PDT are determined by the combination of all components. Each component varies temporally and spatially during PDT, and the variations are mutually dependent on each other. Moreover, components such as the photosensitizer can have great variations in their initial distribution among patients even before PDT treatment. Given this, no well accepted standard PDT dose metric method has been recognized in clinics, although different approaches including explicit, implicit and direct dosimetry have been studied. To tackle the inherently complicated PDT mechanism in order to provide insights into PDT and PDT dosimetry, a theoretical one-dimensional model for aminolevulinic acid (ALA) induced protoporphyrin IX (PpIX)-PDT of human skin was developed and is presented in this thesis. The model incorporates major photophysical and photochemical reactions in PDT, and calculated temporal and spatial distributions of PDT components as well as the detectable emission signals including both sensitizer fluorescence and singlet oxygen luminescence (SOL) using typical clinical conditions. Since singlet oxygen is considered to cause PDT outcomes, the correlations of different PDT dose metrics to average reacted (1O2) "dose" and "dose" at different depths were examined and compared for a wide range of varied treatment conditions. The dose metrics included absolute fluorescence bleaching metric (AFBM), fractional fluorescence bleaching metric (FFBM) and cumulative singlet oxygen luminescence (CSOL), and the varied treatment conditions took into account different treatment irradiances and wavelengths, varied initial sensitizer concentration and distribution, and a wide range of optical properties of tissue. These investigations and comparisons provide information about the complicated dynamic process of PDT such as the induction of tissue hypoxia, photosensitizer photobleaching and possible PDT-induced vascular responses. It was also found that the CSOL is the most robust and could serve as a gold standard for the testing of other techniques. In addition to these theoretical studies, recent progress on the assessment of a novel, more efficient superconducting nanowire single photon detector (SNSPD) for singlet oxygen luminescence detection will be introduced and the current photomultiplier tubes (PMT) system will be briefly described as well. The author participated in the experimental assessments of the SNSPD and analyzed the results shown in this thesis.Doctor of Philosophy (PhD
Perbuatan Melawan Hukum Terhadap Perjanjian Pembiayaan Dengan Jaminan Fidusia Pada Perkara Perdata Nomor 135/Pdt/2014/PT.Pbr (Studi Kasus)
No full textAccording to Article 1365 the Civil Code of every act that harms another person is called an act of lawlessness (onrechtmatige daad). Parties who feel they have been harmed because they were deprived of their rights and interests can submit a lawsuit to the District Court. As with civil cases Number 135 / PDT / 2014 / PT.PBR about illegal acts. Meanwhile, according to the author who became interested in the case No. 135 / PDT / 2014 / PT.PBR, the Plaintiff lost the decision of the Pekanbaru District Court stating that the Defendants were not proven to have committed an unlawful act based on the evidence submitted by the parties before Panel of judges. So that the Plaintiff filed an appeal to the Pekanbaru High Court and the Panel of Judges also upheld the decision issued by the Pekanbaru District Court. The main problem in this study is: How is the occurrence of illegal acts in civil cases Number: 135 / PDT / 2014 / PT.PBR? and How is the Judge's legal considerations in a civil case Number: 135 / PDT / 2014 / PT.PBR? The research method used by the author seen from the type of research is included in normative legal research (doctrinal). Normative legal research is research conducted by studying documents (case studies), namely by studying case files or documents Number: 135 / PDT / 2014 / PT.PBR, whereas when viewed from the nature of the research that is deductive which means that research is intended to provide a detailed, clear and systematic description of the main research problems. From the results of research and discussion, it is known that illegal acts in case Number 135 / PDT / 2014 / PT.PBR are fulfilling the element of unlawful acts in accordance with the law itself, but not against the Defendant but the Plaintiff itself based on evidence evidence available through reconciliation from the Defendant. Judges' judicial considerations in examining and deciding cases Number 135 / PDT / 2014 / PT.PBR are based on the evidence submitted by the Plaintiff and Defendant. The Panel of Judges in providing legal considerations is in accordance with the applicable legal terms and conditions
Tinjauan maslahah dan teori politik hukum terhadap putusan Mahkamah Agung nomor 1876/k/pdt/2018 tentang pemecatan Fahri Hamzah oleh Partai Politik
No full textIndonesia :
Penelitian ini, peneliti menyajikan penelitian tentang Putusan Mahkamah Agung Nomor 1876 K/Pdt/2018 dalam kasus pemecatan Fahri Hamzah sebagai anggota Legislatif oleh partai PKS. Pada kasus ini Fahri Hamzah dipecat keanggotaannya oleh partai PKS karena telah melanggar AD/ART partai. Pada Undang-Undang Nomor 2 Tahun 2011 menjelaskan anggota bisa dipecat apabila melanggar AD/ART partai. Tetapi pada kasus pemecatan Fahri Hamzah ini tidak dijelaskan AD/ART mana yang telah dilanggar oleh Fahri Hamzah kemudian terjadi sengketa antara Fahmi Hamzah dengan Partai PKS. Setelah sampai tahap kasasi yang sebelumnya melalui Pengadilan Negeri Jakarta Selatan dan banding di Pengadilan Tinggi DKI Jakarta , akhirnya Mahkamah Agung mengeluarkan Putusan Mahkamah Agung Nomor 1876 K/Pdt/2018. Penulis menganalisis Putusan Mahkamah Agung Nomor 1876 K/Pdt/2018 dari segi Maslahah sebagai penghubung kemaslahatan negara dan agama juga dari segi teori politik hukum.
Jenis penelitian yang digunakan oleh penulis adalah penelitian normatif. Penulis meneliti dengan bahan hukum Undang-Undang, Putusan-Putusan, Buku serta jurnal dalam mengumpulkan data yang diperlukan selama penelitian. Tujuan dari penelitian ini adalah untuk mengetahui pertimbangan-pertimbangan hakim dalam mengeluarkan Putusan Mahkamah Agung Nomor 1876 K/Pdt/2018 serta mengetahui tinjauan Maslahah dan teori politik hukum terhadap Putusan Mahkamah Agung Nomor 1876 K/Pdt/2018.
Dari Hasil Penelitian, pertimbangan hakim dalam mengeluarkan Putusan Mahkamah Agung Nomor 1876 K/Pdt/2018 yakni mempertahankan hak-hak Fahri Hamzah sebagai anggota legislatif dan juga sebagai warga negara atas kesewenangan pemecatan oleh partai PKS sebagai bentuk penegakkan keadilan. Secara Maslahah Putusan Mahkamah Agung Nomor 1876 K/Pdt/2018 ini dikeluarkan demi kemaslahatan demi kepentingan umum dan mencegah mudharat-mudharat yang lain
Arab :
في هذه الدراسة ، يعرض المؤلف بحثًا حول قرار المحكمة العليا رقم 1876 K / PDT / 2018 في قضية إقالة حزب PKS فهري حمزة كعضو في الهيئة التشريعية. في هذه الحالة ، تم طرد فهري حمزة من عضويته من قبل حزب PKS لأنه انتهك قانون النظام الأساسي / الميزانيات الخاص بالحزب. يوضح القانون رقم 2 لعام 2011 أنه يمكن فصل الأعضاء إذا انتهكوا النظام الأساسي / الميزانيات.الخاص بالحزب. ومع ذلك ، في حالة إقالة فهري حمزة ، لم يتم توضيح ما هو النظام الأساسي/ الميزانيات قد انتهك من قبل فهري حمزة ، ثم وقع نزاع بين فهمي حمزة وحزب PKS. بعد الوصول إلى مرحلة النقض التي كانت في السابق من خلال محكمة مقاطعة جاكرتا الجنوبية والاستئناف أمام محكمة DKI جاكرتا العليا ، أصدرت المحكمة العليا أخيرًا قرار المحكمة العليا رقم 1876 K / PDT / 2018 . يحلل المؤلف قرار المحكمة العليا رقم 1876 K / PDT / 2018 من حيث المصلحة كحلقة وصل لصالح الدولة والدين وكذلك من حيث النظرية السياسية القانونية.
نوع البحث الذي يستخدمه المؤلف هو بحث معياري. يرغب المؤلف في البحث بالمواد القانونية مثل القوانين والقرارات والكتب والمجلات في جمع البيانات اللازمة أثناء البحث. الغرض من هذا البحث هو معرفة اعتبارات القضاة في إصدار قرار المحكمة العليا رقم 1876 K / PDT / 2018 ومعرفة مراجعة مصلحة خالصة من النظرية السياسية القانونية ضد قرار المحكمة العليا رقم 1876 K / PDT / 2018.
من نتائج الدراسة ، كان اعتبار القاضي في إصدار قرار المحكمة العليا رقم 1876 K / PDT / 2018 هو الدفاع عن حقوق فهري حمزة كعضو في الهيئة التشريعية وأيضًا كمواطن للفصل التعسفي من قبل حزب PKS شكل من أشكال دعم العدالة. صالحه صدر قرار المحكمة العليا رقم 1876 K / PDT / 2018 لصالح الجمهور ولمنع الأضرار.
Inggris :
In this study, the author presents research on the Supreme Court's Decision Number 1876 K/Pdt/2018 in the case of the dismissal of Fahri Hamzah as a member of the Legislature by the PKS party. In this case, Fahri Hamzah was dismissed from his membership by the PKS party because he had violated the party's AD/ART. Law Number 2 of 2011 explains that members can be fired if they violate the party's AD/ART. However, in the case of Fahri Hamzah's dismissal, it was not explained which AD/ART had been violated by Fahri Hamzah, then a dispute occurred between Fahmi Hamzah and the PKS Party. After reaching the cassation stage which was previously through the South Jakarta District Court and an appeal at the DKI Jakarta High Court, the Supreme Court finally issued Supreme Court Decision Number 1876 K/Pdt/2018. The author analyzes the Supreme Court Decision Number 1876 K/Pdt/2018 in terms of Maslahah as a liaison for the benefit of the state and religion as well as in terms of Legal Political Theory.
The type of research used by the author is normative research. The author wishes to research with legal materials such as laws, decisions, books and journals in collecting the necessary data during the research. The purpose of this research is to find out the judges' considerations in issuing the Supreme Court Decision Number 1876 K/Pdt/2018 and to find out Maslahah's review and Legal Political Theory against the Supreme Court's Decision Number 1876 K/Pdt/2018.
From the results of the study, the judge's consideration in issuing the Supreme Court Decision Number 1876 K/Pdt/2018 was to defend Fahri Hamzah's rights as a member of the legislature and also as a citizen of the arbitrary dismissal by the PKS party as a form of upholding justice. Maslahah The Supreme Court Decision Number 1876 K/Pdt/2018 was issued for the benefit of the public and to prevent other harms
Early pneumococcal clearance in mice induced by systemic immunization with recombinant BCG PspA-PdT prime and protein boost correlates with cellular and humoral immune response in bronchoalveolar fluids (BALF)
No full text© 2019 The Author(s) An effective immunological response in the lungs during a pneumococcal infection is a key factor to the bacteria clearance and prevention of sepsis. In order to develop broad-range pneumococcal vaccines several pneumococcal proteins and strong adjuvants have been investigated. Previously, we constructed a recombinant BCG (rBCG) strain expressing a fragment of PspA (Pneumococcal surface protein A) fused to PdT (detoxified form of pneumolysin). Immunization of mice with a priming dose of rBCG PspA-PdT followed by a booster dose of rPspA-PdT fused protein induced a high antibody response in the serum and protected mice against lethal challenge. Here, we investigated the humoral and cellular immune response in the Bronchoalveolar lavage fluid (BALF). Immunization of mice with rBCG PspA-PdT / rPspA-PdT induced rapid clearance of bacteria after challenge, an early control of the cellular influx and reduced inflammatory cytokine levels in the BALF. In addition, rBCG PspA-PdT / rPspA-PdT induced higher lymphocyte recruitment to the lungs at 48 h, showing an increased percentage of CD4+ T cells. Furthermore, BALF samples from mice immunized with rBCG PspA-PdT / PspA-PdT showed high binding of IgG2c and enhanced complement deposition on the pneumococcal surface; antibody binding was specific to PspA as no binding was observed to a PspA-knockout strain. Taken together, our results show that the immunization with rBCG PspA-PdT / rPspA-PdT induces humoral and cellular immune responses in the lungs, promotes an early clearance of pneumococci and protects against the systemic dissemination of pneumococci
Kepastian Hukum Perjanjian Perkawinan yang Tidak Didaftarkan (Studi Kasus Putusan Pengadilan No.449/PDT/2016/PT.BDG)
No full textA marital agreement is made to abolish the joint assets between husband and wife. The marital agreement was also made to protect personal assets and facilitate the management of matrimonial assets. The marital agreement must be stated in a notarial deed in written form attended by the parties and witnesses. After issuing the marital agreement deed, it must be registered by the marriage registrar at the Office of Religious Affairs or the Department of Population and Civil Registration to reach the perfect procedures. The registration of marital agreements is an implementation of a publicity principle in Article 29, paragraph (1) of the Marriage Law. However, in practice shows that many parties did not register their marital agreement with the marriage registrar. In this study, the author will analyse Decision No.449/PDT/2016/PT.BDG by considering the provisions in the Civil Code, the Marriage Law, the Constitutional Court Decision Number 69/PUU-XIII/2015, and other related laws. The problems with Decision No.449/PDT/2016/PT.BDG are the embodiment of the judge\u27s decision regarding the existence of joint property between husband and wife which contains a marital agreement in it. Therefore, the author has an interest in knowing the legal certainty of a marital agreement that is not weakened and an analysis of the granting of the existence of joint assets while it is known that there is a marital agreement in Decision No.449/PDT/2016/PT.BDG. In conducting research, the authors use research methods with normative juridical forms. The results of the study show that the marital agreement remains a valid agreement as a statute to the parties who make it even though the marital agreement has never been a marriage registrar. Thus, with the validity of the marital agreement, there should never have been an of assets between husband and wife
TINJAUAN YURIDIS TERHADAP PENOLAKAN PERMOHONAN PAILIT YANG DIAJUKAN OLEH OJK TERKAIT PUTUSAN HAKIM DALAM PERKARA Nomor : 04/PDT-SUS-PAILIT/2015/PN.NIAGA.JKT.PST.Jo No27Pdt.Sus.PKPU/2015/PN.NIAGA.Jkt.Pst.
No full textThis legal research entitled “Judicial Review Against Refusal on Bankruptcy Decision Submitted By The Financial Service Authority Related To Judges Verdict On Case Number 04/Pdt-Sus Pailit/2015/Pn.Niaga.Jkt.Pst. Jo. Number 27/Pdt.Sus.Pkpu/2015/Pn.Niaga.Jkt.Pst”. PT. Asuransi Bumi Asih Jaya is an insurance company which lawsuit for bankruptcy by The Financial Service Authority related to insurance claim payment dispute. This suit proves there is a distrust between client, The Financial Service Authority, and insurance company. This legal research using normative legal method. Normative legal method focusing on positive law in the form of legislation. Normative legal method also using secondary data. After done some research, author reach a conclusion that judges verdict on case Number 04/Pdt-Sus-Pailit/2015/Pn.Niaga.Jkt.Pst. Jo. Number 27/Pdt.Sus.Pkpu/2015/Pn.Niaga.Jkt.Pst are not suitable with the legislations and author suggested that judges especially judges on commercial court could interpret a legislation deeper so it will not causing problems in future
Novos derivados porfirínicos: síntese e potenciais aplicações em PDT
No full textDoutoramento em QuimicaO trabalho apresentado nesta dissertação descreve estudos desenvolvidos
segundo três metodologias para a funcionalização de meso-tetra-arilporfirinas;
uma delas baseada na funcionalização com diazo compostos, outra na reacção de
Suzuki-Miyaura e a terceira na reacção de metátese.
O presente documento é composto por quatro partes distintas.
Na primeira parte são feitas considerações gerais sobre propriedades e aplicações
de macrociclos porfirínicos.
Na segunda parte é apresentado o trabalho realizado na funcionalização de
porfirinas com diazo compostos através de reacções de inserção com um
catalisador de ródio(II). Este estudo envolveu a preparação de duas porfirinas com
grupos O-H e N-H nas posições para dum substituinte meso-fenilo. Os estudos
iniciaram-se com a reacção de 5-(4-hidroxifenil)-10,15,20-trifenilporfirinatozinco(II)
com diazoacetato de etilo na presença de Rh2(OAc)4. Obteve-se o produto
esperado de inserção com bons rendimentos. A reacção de 5-(4-aminofenil)-
10,15,20-trifenilporfirinatozinco(II) com esse diazo composto na presença de
Rh2(OAc)4 mostrou um perfil diferente do da reacção com o outro porfirinato.
Foram obtidos três produtos, a saber: produto de bis-inserção e dois outros
contendo o grupo funcional amida. Este capítulo descreve ainda a síntese de
glicoporfirinas e de glicoclorinas através de reacções de inserção e de
ciclopropanação envolvendo, respectivamente, os complexos 5-(4-hidroxifenil)-
10,15,20-trifenilporfirinatozinco(II) e 5,10,15,20-
tetraquis(pentafluorofenil)porfirinatozinco(II) com α-diazoacetatos com substituintes
sacarídicos. Foram usados, como catalisadores, Rh2(OAc)4 e CuCl,
respectivamente, na reacção de inserção e na de ciclopropanação.
Tendo em vista a sua aplicação em PDT, os novos produtos foram
descomplexados e a unidade glicosídica foi desprotegida. Estudos de geração de
oxigénio singuleto mostraram que os compostos obtidos são bons geradores
dessa espécie citotóxica. Foram também realizados estudos de avaliação da
actividade fotodinâmica em células humanas tumorais HeLa e em células
humanas saudáveis HaCaT. Estudos de viabilidade celular, após tratamento
fotodinâmico, mostraram que as glicoclorinas são mais eficazes na fotoinactivação
das células tumorais. Apenas o derivado da clorina com a unidade de
galactose mostrou selectividade para a linha celular tumoral, inibindo o
crescimento desta e não causando efeito significativo na linha celular saudável.
Este fotossensibilizador não foi tóxico na ausência de luz e depois do tratamento
fotodinâmico e em condições sub-letais, provocou vacuolização citoplasmática e
retracção pronunciada nas células tumorais, enquanto que nas células saudáveis
os danos sofridos foram escassos. Nos estudos de localização celular este
fotossensibilizador localizou-se na membrana citoplasmática e nos lisossomas
tanto nas células HeLa como nas HaCaT.
Na terceira parte deste trabalho são descritos os resultados obtidos nos estudos
de funcionalização de porfirinas através da reacção de Suzuki-Miyaura. O
complexo 2-(4,4,5,5,-tetrametil-1,3,2-dioxaborolan-2-il)-5,10,15,20-
tetrafenilporfirinatozinco(II) foi o composto escolhido como reagente de partida.
Usando a reacção de Suzuki foi possível sintetizar complexos β-bromoarilporfirínicos
em bons rendimentos. Estes complexos foram sujeitos à reacção de
Suzuki com pinacolborano, tendo sido possível obter os produtos de acoplamento
esperados e ainda derivados diméricos de complexos porfirínicos ligados por
unidades fenileno. Esta metodologia reacional, catalisada por paládio, permitiu
ainda sintetizar novos derivados quinolona-porfirina através da reacção do
complexo porfirínico β-borilado anteriormente referido com bromo-quinolonas Nsubstiuídas
com grupos alquílicos e glicosídicos. Deste modo foram obtidos
derivados quinolona-porfirina em bons rendimentos. Com vista a realizar estudos
de potencial aplicação em PACT, foram hidrolisados os grupos éster da unidade
de quinolona e clivados os grupos protectores das unidades glicosídicas desses
derivados. No estudo por MS Tandem (MS/MS) foi possível verificar que os
isómeros dos derivados quinolona-porfirina sofrem as mesmas vias de
fragmentação, confirmando as suas estruturas análogas. Foi possível ainda
distinguir os derivados em que a unidade de porfirina está ligada à quinolona
através da posição C-6 da quinolona daqueles em que a unidade de porfirina está
ligada à quinolona através da sua posição C-7.
Os estudos de geração de oxigénio singuleto mostraram que as porfirinas β-
substituídas com unidades de quinolona são melhores geradoras desta espécie
citotóxica do que a tetrafenilporfirina e que a eficiência que têm em gerar essa
espécie é afectada pela posição da ligação entre a porfirina e a quinolona, assim
como com o tipo do N-substituinte da quinolona. As bases livres dos conjugados
quinolona-porfirinatos foram testadas como fotossensibilizadores em PACT em
células do parasita Leishmania Braziliensis, tendo-se observado que estes
compostos têm capacidade para fotoinactivar este parasita.
Na quarta parte deste trabalho são descritos os resultados dos estudos de
funcionalização de porfirinas através da reacção de metátese com catalisador de
Grubbs, visando a obtenção de novos macrociclos com grupos triazolilo. Verificouse
que a eficiência da reacção de metátese cruzada entre 2-vinil-5,10,15,20-
tetrafenilporfirinatozinco(II) e 4-vinil-1,2,3-triazóis N-substituídos dependia das
condições reaccionais e do triazol usado em cada caso. Foi possível ainda concluir
que o impedimento estéreo das espécies envolvidas é um dos responsáveis pelo
ciclo catalítico prosseguir por uma via secundária, originando uma espécie de
ruténio pouco eficiente como catalisador. Este estudo foi estendido à reacção dos
4-vinil-1,2,3-triazois seleccionados com 2-butadienil-5,10,15,20-
tetrafenilporfirinatoniquel(II); em cada caso foi possível obter uma mistura de
isómeros dos derivados triazol-porfirina, geralmente em maiores rendimentos
globais do que na reacção com 2-vinil-5,10,15,20-tetrafenilporfirinatozinco(II). Este
facto será indicativo de que a reacção de metátase com esse derivado porfirínico
segue, predominantemente, a via mais eficiente.The work presented in this dissertation reports studies carried out according three
different methodologies for the functionalization of meso-tetra-arylporphyrins: one
is related with the functionalization with diazo compounds, another one considers
the Suzuki-Miyaura approach and the third one the metathesis reaction. This
document has four parts.
The first one relates the main properties and applications of porphyrin derivatives.
The second part reports results on studies carried out for the functionalization of
porphyrins with diazo compounds through insertion reactions catalyzed by a
rhodium-based catalyst. This study involved the preparation of two porphyrins with
OH and NH groups in the p-position of one meso-phenyl substituent of those
macrocycles. Reaction of 5-(4-hydroxyphenyl)-10,15,20-
triphenylporphyrinatozinc(II) with ethyl diazoacetate in the presence of Rh2(OAc)4
gave rise to the expected insertion product in good yields. In the reaction of 5-(4-
aminophenyl)-10,15,20-triphenylporphyrinatozinc(II) with such diazo compound in
the presence of Rh2(OAc)4 a different profile was observed. Three products were
obtained: one corresponding to the bis-insertion product and the other two having
each one an amide function. This part of the thesis also describes the synthesis of
glycoporphyrins and glycochlorins through insertion and cyclopropanation
methodologies, respectively, in reactions with 5-(4-hydroxyphenyl)-10,15,20-
triphenylporphyrinatozinc(II) and 5,10,15,20-
tetrakis(pentafluorophenyl)porphyrinatozinco(II) with carbohydrate substituted α-
diazoacetates. As catalysts were used Rh2(OAc)4 for the insertion reactions and
CuCl for the cyclopropanation ones. Having in mind their potential applications in
PDT, the new derivatives obtained were demetallated and the sugar units were
deprotected. Studies on the singlet oxygen generation by the new compounds have
shown that these derivatives are good generators of that cytotoxic species. The
new compounds were tested as photosensitisers in PDT, on a cancer cellular line,
HeLa and on a normal cell line, HaCaT. Studies on cell viability after PDT treatment
have shown that glycochlorins are more effective in the photoinactivation of the
tumor cell line. Only the galactose-chlorin derivative showed selectivity for HeLa
cells, inhibiting the growth of this tumoral cell line and causing no significant effect
on the normal cell line. This photosensitiser was not toxic in the absence of light
and it caused cytoplasmatic vacuolization and pronounced retraction in tumoral cell
line, while in HaCaT the damages were scarce. In the study of cellular localization,
this photosensitiser was located in the cytoplasmic membrane and lysosomes in
both HeLa and HeCat cells.
The third part of this dissertation describes the results obtained on the
functionalization of porphyrins under the Suzuki-Miyaura reaction conditions. The
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,10,15,20-
tetraphenylporphyrinatozinc(II) was chosen for being used in this reaction. Using
the Suzuki methodology it was possible to synthesize β-bromo-arylporphyrinic
complexes in good yields. These brominated porphyrinates were used in the
Suzuki reaction with pinacol borane; it was possible to obtain novel coupling
product derivatives and also porphyrin dimers linked by phenylene units. This
reaction catalyzed by palladium also allowed us to synthesize new quinoloneporphyrin
derivatives by the reaction of the β-borylated porphyrinic complex with Nsubstituted
bromo-quinolones with alkyl and glycosyl groups affording quinoloneporphyrin
derivatives in good yields. It was also performed the hydrolysis of the
ester groups of the quinolone moieties and the deprotection of the glycosidic units
of the quinolone-porphyrin derivatives, having in mind their potential application in
PACT. In the electrospray tandem mass spectrometry (MS/MS) of the quinoloneporphyrin
derivatives it was possible to verify that isomeric porphyrin-quinolone
derivatives give rise to similar fragmentation pathways, confirming their analogous
structures. Due to the relative abundance of some peaks it was possible to
distinguish between derivatives with the porphyrin moiety linked at C-6 of the
quinolone unit from those having the porphyrin moiety linked to the 7-position of the
quinolone moiety. Singlet oxygen studies have shown that all the β-substituted
porphyrin-quinolones are better singlet oxygen generators than TPP and that the
efficiency of these compounds to generate singlet oxygen is affected by the linkage
position between the porphyrin and the quinolone moieties, and also by the type of
the N-substituent of the quinolone group. The free bases of quinolone-porphyrin
conjugates were tested as photossensitizers in PACT against the Leishmania
Braziliensis parasite cells; it was observed that these compounds are able to
photoinactivate such parasite.
photoinactivate such parasite.
In the fourth part of this document it is described the results obtained in the study of
the functionalization involving triazolyl groups of porphyrin macrocycles by the
metathesis reaction using the Grubbs catalyst. It was found that the reaction
between 2-vinyl-5,10,15,20-tetraphenylporphyrinatozinc(II) and N-substituted 4-
vinyl-1,2,3-triazoles are dependent on the reaction conditions and on the triazole.
The best conditions found were used for the synthesis of new triazole-porphyrin
derivatives. The study of the reaction mechanism has shown that the steric
hindrance between the two species involved is a main reason for the catalytic cycle
to continue on a path characterized by the poor efficiency. This study of the
metathesis reaction was extended to the reaction of selected N-substituted 4-vinyl-
1,2,3-triazoles with 2-butadienyl-5,10,15,20-tetraphenylporphyrinatonickel(II) (a
porphyrinic complex with less steric hindrance) affording a mixture of isomeric
triazole-porphyrin derivatives, in higher global yields than the reactions with 2-vinyl-
5,10,15,20-tetraphenylporphyrinatozinc(II). This might indicate that the metathesis
reactions with the former porphyrin follows, predominantly, the more efficient route
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