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The complex natural product paclitaxel (Taxol®), first isolated from Taxus brevifolia, is a member of a large family of taxane diterpenoids. Paclitaxel is extensively used for the treatment of solid tumors, particularly those of the breasts and ovaries. In order to obtain additional information about the mechanism of action of paclitaxel and the environment of the paclitaxel-binding site, several fluorescent analogs of paclitaxel were synthesized, and their biological activities have been evaluated. For the investigation of possible synergistic effects, concurrent modifications on selected positions have been performed and their biological evaluation were studied. / Ph. D.

Prostate cancer is the most common non-skin cancer for men in America. The androgen receptor exerts transcriptional activity and plays an important role for the proliferation of prostate cancer cells. Androgen receptor ligands bind the androgen receptor and inhibit its transcriptional activity effectively. However, prostate cancer can progress to hormone refractory prostate cancer (HRPC) to avoid this effect. Chemotherapies are currently the primary treatments for HRPC. Unfortunately, none of the available chemotherapies are curative. Among them, paclitaxel and docetaxel are two of the most effective drugs for HRPC. More importantly, docetaxel is the only form of chemotherapy known to prolong survival in the HRPC patients. We hypothesized that the conjugation of paclitaxel or docetaxel with an androgen receptor ligand will overcome the resistance mechanism of HRPC. Eleven conjugates were designed, synthesized and biologically evaluated. Some of them were active against androgen-independent prostate cancer, but they were all less active than paclitaxel and docetaxel. Discodermolide is a microtubule interactive agent, and has a similar mechanism of action to paclitaxel. Interestingly, discodermolide is active against paclitaxel-resistant cancer cells and can synergize with paclitaxel, which make it an attractive anticancer drug candidate. Understanding the bioactive conformation of discodermolide is important for drug development, but this task is difficult due to the linear and flexible structure of discodermolide. Indirect evidence for the orientation of discodermolide in the tubulin binding pocket can be obtained from fluorescence spectroscopy of the discodermolide tubulin complex. For this purpose, we designed and synthesized a simplified fluorescently labeled discodermolide analog, and it was active in the tubulin assembly bioassay. In addition, a conformationally constrained discodermolide was designed to mimic the bioactive conformation according to computational modeling. The synthetic effort was made, but failed during one of the final steps. / Ph. D.

Paclitaxel is one of the most successful anti-cancer drugs, particularly in the treatment of breast cancer and ovarian cancer. For the investigation of the interaction between paclitaxel and MD-2 protein, and development of new antagonists for lipopolysaccharide, several C10 A-nor-paclitaxel analogs have been synthesized and their biological activities have been evaluated. In order to reduce the myelosuppression effect of the paclitaxel, several C3â ² and C4 paclitaxel analogs have been synthesized and their biological evaluation have been studied. / Master of Science

O paclitaxel é utilizado amplamente no carcinoma de ovário, nos casos refratários de carcinoma de endométrio e quimioterapia exclusiva para carcinoma avançado de colo uterino. A associação de paclitaxel a uma nanoemulsião rica em colesterol, denominada LDE, mostrou toxicidade menor e aumento da atividade antitumoral do fármaco em cobaias. No presente estudo, investigou-se os parâmetros farmacocinéticos do oleato de LDE-paclitaxel e a habilidade da LDE de concentrar o fármaco no tumor em oito pacientes com câncer do trato genital feminino. O oleate de paclitaxel associado a LDE é estável na circulação e tem uma meia-vida plasmática maior do que o paclitaxel comercial. A LDE concentra 3,6 mais paclitaxel em tecidos tumorais do que nos tecidos normais. Esta associação parece ser uma alternativa no tratamento dos tumores ginecológicos / A cholesterol-rich nanoemulsion termed LDE concentrates in cancer tissues after injection into the bloodstream. The association of a derivatized paclitaxel to LDE showed lower toxicity and increased antitumoral activity as tested in mice. Here, the pharmacokinetics of LDE-paclitaxel oleate and the ability of LDE to concentrate the drug in the tumor were investigated in eight patients with gynecologic cancers. Fractional clearance rate (FCR) and pharmacokinetic parameters were calculated by compartmental analysis. Also, specimens of tumors and the normal tissues were excised during the surgery for radioactivity measurement. LDE concentrates 3.5 more paclitaxel in malignant tissues than in the normal tissues. Therefore, association to LDE is an interesting strategy for using paclitaxel to treat gynecologic cancers

O paclitaxel é utilizado amplamente no carcinoma de ovário, nos casos refratários de carcinoma de endométrio e quimioterapia exclusiva para carcinoma avançado de colo uterino. A associação de paclitaxel a uma nanoemulsião rica em colesterol, denominada LDE, mostrou toxicidade menor e aumento da atividade antitumoral do fármaco em cobaias. No presente estudo, investigou-se os parâmetros farmacocinéticos do oleato de LDE-paclitaxel e a habilidade da LDE de concentrar o fármaco no tumor em oito pacientes com câncer do trato genital feminino. O oleate de paclitaxel associado a LDE é estável na circulação e tem uma meia-vida plasmática maior do que o paclitaxel comercial. A LDE concentra 3,6 mais paclitaxel em tecidos tumorais do que nos tecidos normais. Esta associação parece ser uma alternativa no tratamento dos tumores ginecológicos / A cholesterol-rich nanoemulsion termed LDE concentrates in cancer tissues after injection into the bloodstream. The association of a derivatized paclitaxel to LDE showed lower toxicity and increased antitumoral activity as tested in mice. Here, the pharmacokinetics of LDE-paclitaxel oleate and the ability of LDE to concentrate the drug in the tumor were investigated in eight patients with gynecologic cancers. Fractional clearance rate (FCR) and pharmacokinetic parameters were calculated by compartmental analysis. Also, specimens of tumors and the normal tissues were excised during the surgery for radioactivity measurement. LDE concentrates 3.5 more paclitaxel in malignant tissues than in the normal tissues. Therefore, association to LDE is an interesting strategy for using paclitaxel to treat gynecologic cancers

?rea de concentra??o: Ci?ncias farmac?uticas. / Data de aprova??o ausente. / Disponibiliza??o do conte?do parcial, conforme Termo de Autoriza??o no trabalho. / Submitted by Jos? Henrique Henrique (jose.neves@ufvjm.edu.br) on 2016-12-20T19:20:11Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) sara_pacelli_sousa_marcial_parcial.pdf: 166236 bytes, checksum: c01c4f087337cd82c64b06b90a1cc4dc (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2017-01-17T18:55:36Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) sara_pacelli_sousa_marcial_parcial.pdf: 166236 bytes, checksum: c01c4f087337cd82c64b06b90a1cc4dc (MD5) / Made available in DSpace on 2017-01-17T18:55:36Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) sara_pacelli_sousa_marcial_parcial.pdf: 166236 bytes, checksum: c01c4f087337cd82c64b06b90a1cc4dc (MD5) Previous issue date: 2016 / Funda??o de Amparo ? Pesquisa do Estado de Minas Gerais (FAPEMIG) / O paclitaxel (PTX) ? um agente quimioter?pico que tem uma importante fun??o no tratamento de v?rios tipos de c?ncer, especialmente o c?ncer de mama. No entanto, a baixa solubilidade do PTX em meio aquoso (coeficiente de parti??o log = 3,96) representa uma limita??o para a administra??o intravenosa. A formula??o convencional do PTX cont?m uma alta concentra??o de Cremofor-EL? (derivado polietoxilado do ?leo de r?cino), o qual induz significante toxicidade, restringindo sua utiliza??o cl?nica. A encapsula??o do PTX em sistema de libera??o de f?rmacos pode melhorar a absor??o e aumentar a sua efic?cia terap?utica. Neste estudo, tr?s diferentes nanossistemas lip?dicos contendo PTX, nanopart?culas lip?dicas s?lidas (NLS), nanoemuls?o (NE) e carreadores lip?dicos nanoestruturados (CLN) foram preparados e as propriedades f?sico-qu?micas e a atividade citotoxicidade in vitro foram avaliadas. Em rela??o ao di?metro m?dio, o CLN branco mostrou valor de di?metro aproximadamente 2 e 1,7 vezes menor que os obtidos para NLS e NE, respectivamente. A presen?a de PTX levou a um aumento significativo no di?metro das part?culas em todos os sistemas avaliados, exceto no NE. Al?m disso, o aumento da concentra??o do f?rmaco (0,01% para 0,025%) produziu um aumento do di?metro para a prepara??o de CLN. Todas as formula??es com PTX mostraram ?ndice de polidispers?o superior a 0,3, exceto para NE-PTX na concentra??o do f?rmaco igual a 0,01% (p/v). Valores negativos de potencial zeta foram observados para todas as formula??es avaliadas. CLN-PTX foi o sistema mais est?vel ap?s armazenado por 30 dias a 4 ?C. O estudo de citotoxicidade nas linhagens celulares de c?ncer de mama (MDA-MB-231 e MCF-7) demonstrou atividade citot?xica mais pronunciada para CLN-PTX do que para o PTX livre em ambos as linhagens celulares do tumor. Baseado nesses resultados, CLN-PTX parece ser uma ferramenta potencial para o tratamento do c?ncer de mama. / Disserta??o (Mestrado) ? Programa de P?s-gradua??o em Ci?ncias Farmac?uticas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, [2016]. / Paclitaxel (PTX) is a chemotherapeutic agent that plays an important role in the treatment of several types of human cancer, especially breast cancer. However, the low solubility of PTX in aqueous medium (partition coefficient log of 3.96) represents a barrier for intravenous administration. The conventional PTX formulation contains a high concentration of Cremophor-EL? (polyethoxylated castor oil), which is associated with significant toxicities restricting its clinical use. The encapsulation of the PTX in drug delivery systems could improve the uptake and increase its therapeutic efficacy. In this study, three different lipid nanosystems containing PTX, solid lipid nanoparticle (SLN), nanoemulsion (NE), and nanostructured lipid carrier (NLC) were prepared, and the physicochemical properties and in vitro cytotoxic activity were evaluated. Concerning the mean diameter, NLC blank showed diameter values approximately 2 and 1.7-fold lower than those obtained for SLN and NE, respectively. The presence of PTX leads to a significant increase in the particle diameter in all systems evaluated, except NE. In addition, increases in drug concentration (0.01% to 0.025%) produced an enhanced diameter for NLC preparation. All formulations containing PTX showed PI higher than 0.3, except for NE-PTX at drug concentration equal to 0.01% (w/v). Negative zeta potential values were observed in all formulations evaluated. NLC-PTX was the system more stable after storage for 30 days at 4 oC. The cytotoxicity studies on breast cancer cell lines (MDA-MB-231 and MCF-7) demonstrated cytotoxic activity more pronounced for NCL-PTX than for free PTX for both tumor cell lines. Thus, the results showed that NCL-PTX seems to be a potential tool for the treatment of breast cancer.