Th. 3e cycle--Phys. du solide--Grenoble 1, 1981. N°: 12.

Nucleoside polyphosphates and their conjugates, such as nucleoside triphosphates, nucleoside tetraphosphates, sugar nucleotides, dinucleoside pyro- and higher order polyphosphates, 2’,3’-cyclic nucleoside monophosphates, and 2´-deoxynucleoside-5´-tetraphosphates in which a fluorescent label is attached to the terminal phosphate have many biological roles and have been developed into drugs. However, their synthesis remains a challenge. Several novel and efficient approaches to the synthesis of nucleoside polyphosphates and their conjugates were developed. In the first approach dinucleoside polyphosphates (NpnN’s where n = 2-4) are prepared via in situ trifluoroacetate protection and imidazolium activation of nucleoside 5’-monophosphates. This methodology was also used to prepare a substrate-intermediate analog of the reaction catalyzed by cytidine triphosphate synthase (CTPS) a recognized target for the development of antineoplastic, antiviral and antiprotozoal agents. The second approach uses sulfonylimidazolium salts as key reagents for generating highly reactive nucleotide donors. The procedure is rapid, produces a wide variety of nucleoside polyphosphates and their conjugates in high yield, does not require protection and subsequent deprotection of the nucleotide donors or acceptors and can be used to activate nucleoside mono-, di-, and triphosphates and a wide variety of acceptors. Finally an entirely new approach to the synthesis of nucleoside tetraphosphates (Np4’s), dinucleoside pentaphosphates (Np5N’s) and nucleoside tetraphosphates in which a fluorescent dye is attached to the terminal phosphate is described employing an activated form of cyclic trimetaphosphate as a novel phosphorylating agent. Attempts to prepare nucleoside triphosphates by subjecting unprotected ribonucleosides and 2’-deoxyribonucleosides to activated cyclic trimetaphosphate failed. Instead nucleoside 2’,3’-cyclic phosphates were obtained in good yield with the ribonucleoside substrates. This represents a new and convenient approach to the synthesis of this class of compounds.

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2016-03-17T16:57:36Z No. of bitstreams: 1 PDF - Silvana Cartaxo da Costa.pdf: 2220034 bytes, checksum: fa6fe0b10616cb9ed70f24ac4dc15d62 (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2016-07-22T15:01:05Z (GMT) No. of bitstreams: 1 PDF - Silvana Cartaxo da Costa.pdf: 2220034 bytes, checksum: fa6fe0b10616cb9ed70f24ac4dc15d62 (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2016-07-22T15:01:16Z (GMT) No. of bitstreams: 1 PDF - Silvana Cartaxo da Costa.pdf: 2220034 bytes, checksum: fa6fe0b10616cb9ed70f24ac4dc15d62 (MD5) / Made available in DSpace on 2016-07-22T15:01:16Z (GMT). No. of bitstreams: 1 PDF - Silvana Cartaxo da Costa.pdf: 2220034 bytes, checksum: fa6fe0b10616cb9ed70f24ac4dc15d62 (MD5) Previous issue date: 2014-05-23 / The development of a colon-specific delivery system using polymeric microparticles has received great attention in the pharmaceutical field. An interesting group of polymers with potential properties in this area are the hemicellulose. Xylan is a hemicellulose that has the ability to pass through the digestive tract unchanged and its complex structure requires enzymes that are produced specifically by the human colonic microflora, which makes it an interesting raw material in the production of target drug delivery systems. The microparticulate systems can be developed by various techniques. The interfacial crosslinking polymerization is one of the major techniques to produce polysaccharide based microparticles. However, the use of highly toxic crosslinkers often makes the use of this technique limited. The sodium trimetaphosphate (TSTP), a low toxic crosslinking agent, has no adverse effects reported on human beings. The aim of this study was to develop xylan microparticles using sodium trimetaphosphate. The microparticles were characterized by optical microscopy, SEM, XRD and FT -IR. The influence of different parameters on the diameter of the microparticles was analyzed during their development. Toxicity studies against Artemia saline Leach were made to compare the microparticles produced with terephthaloyl chloride and sodium trimetaphosphate. Xylan microparticles showed to be spherical shape, well individualized and with a smooth surface. All different parameters influenced the in size of the microparticles. The FT-IR spectrum of microparticles was similar to xylan, but with the presence of the peak at 1258 cm -1 , which is typical of phosphate ester bonds, that can be attributed to the bond between TSTP and xylan during the crosslinking process. The xylan microparticles produced in this work showed no toxicity at the concentration studied. It be concluded that TSTP was able to produce xylan microparticles with well defined physicochemical characteristics and low toxicity. / O desenvolvimento de um sistema de liberação cólon-específica utilizando micropartículas poliméricas têm recebido grande atenção no campo farmacêutico. Um grupo interessante de polímeros com potenciais propriedades nessa área são as hemiceluloses. A xilana é uma hemicelulose que tem a capacidade de passar através do trato digestivo inalterada e sua complexa estrutura requer enzimas que são produzidas especificamente pela microflora colônica humana, o que a torna uma interessante matéria-prima na área produção de sistemas de liberação de fármacos. Os sistemas microparticulados podem ser desenvolvidos por várias técnicas. A reticulação polimérica interfacial é uma das principais técnicas para produção de micropartículas à base de polissacarídeos. Porém o uso de reticulantes de alta toxicidade muitas vezes torna o uso desta técnica limitada. O trimetafosfato de sódio (TSTP) é um reticulante de baixa toxicidade, sem efeitos adversos relatados em seres humanos. Esse trabalho teve como objetivo desenvolver micropartículas de xilana utilizando TSTP. As micropartículas foram caracterizadas por microscopia óptica, MEV, DRX e FT-IR. Estudos de toxicidade frente à artemia salina Leach foram feitos para comparar as micropartículas produzidas com cloridrato de tereftaloíla e trimetafosfato de sódio. As micropartículas de xilana apresentaram forma esférica, bem individualizada e com superfície bem definida. Todos os diferentes parâmetros influenciaram no tamanho das micropartículas. O espectro de FT-IR das micropartículas foi semelhante ao da xilana, porém com a presença de um pico em 1258 cm -1 , que é típico de ligações éster-fosfato, que pode ser atribuído a ligação entre TSTP e a xilana durante o processo de reticulação. As micropartículas de xilana produzidas neste trabalho não apresentaram toxicidade na concentração estudada. Podemos concluir que o TSTP foi capaz de produzir micropartículas de xilana com cracterísticas fisico-químicas bem definidas e de baixa toxicidade.