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The plant kingdom contributes significantly to the natural products that are used for the treatment of a large number of ailments and disease across the globe. Included in these species is the Helichrysum genus (Asteraceae), which comprises of more then 600 species across Africa of which 244 species are found in South Africa. Helichrysum species are used in many cases for the treatment of coughs, colds, fever, infection, headaches, menstrual pain and are also very popular for wound dressing due to their potential antibacterial properties. The most common Helichrysum species used in traditional medicine and for several medicinal purposes are H. cymosum, H. odoratissimum, H. petiolare and H. nudifolium. Previously published research has shown that several of the Helichrysum species do have antimicrobial activity with the most relevant to this study being the discovery of antiviral activity of H. aureonitens against herpes simplex virus type 1 (HSV-1) as well as the reports of anti-HIV (human immunodeficiency virus) activity of several Helichrysum species. With this knowledge, a more in-depth study was initiated to identify the possible active constituents in South African Helichrysum species against HIV. Due to the need to speed up drug discovery especially against epidemic diseases like HIV, this study investigated a new tool (nuclear magnetic resonance (NMR) – based metabolomics) to speed up drug discovery form natural products especially when anti-viral constituents are investigated. odoratissimum, H. petiolare and H. nudifolium. Previously published research has shown that several of the Helichrysum species do have antimicrobial activity with the most relevant to this study being the discovery of antiviral activity of H. aureonitens against herpes simplex virus type 1 (HSV-1) as well as the reports of anti-HIV (human immunodeficiency virus) activity of several Helichrysum species. With this knowledge, a more in-depth study was initiated to identify the possible active constituents in South African Helichrysum species against HIV. Due to the need to speed up drug discovery especially against epidemic diseases like HIV, this study investigated a new tool (nuclear magnetic resonance (NMR) – based metabolomics) to speed up drug discovery form natural products especially when anti-viral constituents are investigated. In this study very promising anti-HIV results were obtained from several aqueous extracts (1:1 methanol/water) using a full virus model i.e. Helichrysum populifolium (IC50 12 μg/ml), H. appendiculatum (IC50 17 μg/ml), H. cymosum ssp. clavum (IC50 19 μg/ml), H. oxyphyllum (IC50 19 μg/ml) and H. cymosum ssp. cymosum (IC50 21 μg/ml). With the use of NMR-based metabolomics and multivariate data analysis (MVA) the specific characteristic that differentiated the active extracts from the non-active extracts was identified by making use of Orthogonal Projections to Latent Structures – Discriminant Analysis (OPLS-DA). This characteristic was then used as a “blue print” or “fingerprint” to guide the process of fractionation and purification. H. populifolium showed the highest anti-HIV activity and thus was selected as the candidate extract for further analysis. After a very quick and simple chromatographic fractionation process, seven fractions were compared against the activity profile by making use of their NMR profiles, which then visually indicated which of the fractions had the highest similarity. Fraction 6 had the most similar “fingerprint”. The compounds of this active fraction were then identified with the use of liquid chromatography – ion trap – time of flight (LC-IT-TOF) for quick identification. The analysis revealed the presence of five chlorogenic type compounds, 3,4-dicaffeoyl quinic acid (DCQA), 3,5-DCQA, 4,5-DCQA, 1,3,5- tricaffeoyl quinic acid (TCQA) and 5-malonyl-1,3,4-TCQA of which several are well known to have anti-HIV activity ranging from 0.85μM to 12μM. We were thus able to show with this study the possibility of using NMR-based metabolomics guided fractionation to guide the process of fractionation and identification from an active characteristic profile to the active constituents within the active H. populifolium extract. / Thesis (PhD)--University of Pretoria, 2013. / gm2014 / Plant Science / unrestricted

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Orientador: Lúcia Helena Brito Baptistella / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-16T21:00:20Z (GMT). No. of bitstreams: 1 Prando_Alessandra_M.pdf: 6403729 bytes, checksum: ad4c9b72f3570ace54e72daf35771fac (MD5) Previous issue date: 2007 / Resumo: As lactamas, de um modo geral, são de bastante interesse como alvos sintéticos, pois podem apresentar ampla variedade de funções em substratos biológicos. Este trabalho teve como objetivo a preparação de heterociclos nitrogenados, no caso lactamas, a partir do ácido quínico 1. Estas seriam inéditas e, além disso, não existem descrições na literatura de preparação de lactamas a partir do ácido quínico. A rota proposta sugere a introdução do nitrogênio via uma aminólise assistida por microondas, após manipulações químicas no grupo carboxílico inicial. A hidroxiamida formada, aqui representada como 3, foi utilizada para reações visando a formação das lactamas 4 e 7, que seriam provenientes de uma ciclização intramolecular utilizando o nitrogênio da amida como nucleófilo em reação de SN2. Com a introdução da função nitrogenada, duas seqüências sintéticas foram exploradas visando a reação de ciclização intramolecular: uma utilizando o C3 do ácido quínico como centro eletrofílico, que levaria a 4, e a outra utilizando o C5, que levaria a 7. Para uma ciclização em C3, vários testes foram realizados, mas para se chegar a um bom grupo abandonador nesta posição os resultados não foram satisfatórios. Para uma ciclização em C5 foi necessário primeiramente a inversão da estereoquímica neste centro e os melhores resultados foram obtidos via uma seqüência oxidação-redução. Após introdução de um grupo abandonador nesta posição, tratamento em meio básico levou à formação da lactama almejada. A seqüência proposta pode abrir novas alternativas para a preparação de outras lactamas e também de derivados das 4-hidroxiprolinas inéditos. / Abstract: The lactams are very interesting as synthetic targets, especially because they can show a wide variety of functions on biological substrates. This work aimed the preparation of nitrogen heterocycles, in this case lactams, from quinic acid. Their structures are unprecedented, and to the best of our knowledge, there are no reports of the preparation of lactamas from quinic acid in the literature The proposed plan suggests the introduction of the nitrogen via an aminolyses reaction assisted by microwaves of an advanced intermediate. The hydroxyamide formed, here represented as 3, was used for reactions aiming the formation of the lactams skeletons 4 and 7, which would be obtained from an intramolecular using the nitrogen of the amide group as a nucleophile on a SN2 reaction. After the introduction of nitrogenated function, two synthetic sequences were explored aiming the intramolecular cyclisation reaction: one using the C3 of quinic acid as an electrophilic center, which would lead to 4, and other using the C5, which would lead to 7. In order to make the cyclisation reaction on C3, several tests were performed but the results were not satisfactory. On the other hand, for the cyclisation on C5, it was necessary, first of all, the stereochemical inversion in this center, and best results were achieved by an oxidation-reduction sequence. After the introduction of a leaving group in this position, treatment using base led the formation of desired lactam. The proposed sequence should open new alternatives for the preparation of other lactams and also new derivatives of 4-hidroxiprolines. / Mestrado / Quimica Organica / Mestre em Química

Orientador: Lucia Helena Brito Baptistella / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-08T22:53:36Z (GMT). No. of bitstreams: 1 Jorge_AndredeCarvalho_M.pdf: 8483799 bytes, checksum: cbe192b8fe9d903f29cd3c2171475ffc (MD5) Previous issue date: 2006 / Resumo: O ácido quínico 1 é um metabólico de planta de ampla ocorrência natural que teve seu uso limitado no passado como precursor quiral em síntese de múltiplas etapas. Essa aplicação mudou em anos mais recentes quando várias publicações demonstraram toda a potencialidade sintética do seu esqueleto quiral altamente funcionalizado. O objetivo deste trabalho é a utilização de 1 para a síntese de biciclos furanofurona saturados e/ou insaturados com substituintes na junção dos anéis. O interesse nesses esqueletos bicíclicos se deve ao enorme potencial de atividade biológica que eles possuem, já que são idênticos àqueles encontrados em alguns compostos naturais isolados de plantas da família Annonaceae. Esses compostos são pertencentes a um grupo de moléculas conhecido como estiril lactonas, cujos membros, em sua grande maioria, apresentam significantes atividades citotóxicas em relação a células tumorais humanas. A seqüência proposta pode abrir novas alternativas para a preparação de análogos inéditos na serie das estiril lactonas, explorando a possibilidade de um aumento de cadeia através de uma reação de Wittig em carbonila de lactona. Estes novos análogos devem também ser submetidos a teste antiproliferativos, visando a análise de suas possíveis atividades farmacológicas. Os estudos efetuados permitem afirmar que a transformação do sistema ácido quínico em furanofuronas saturadas é bastante viável. A partir de 1 não foi possível a preparação do biciclo furanofurona insaturado 2, mas a rota proposta para os derivados furanofurona saturados 3, 4 e 5 se mostrou bastante versátil, abrindo possibilidades para a preparação de outros tipos de derivados. / Abstract: Quinic acid 1 is a plant metabolite widespread in nature that had in the past a limited use as a chiral precursor on organic synthesis. This application changed in recent years, and now several publications has shown the enormous synthetic potential of its highly functionalized skeleton. The purpose of this work is the use of 1 for the synthesis of furanefurone saturated and/or unsaturated bicycles with substitutes in the ring junction. The interest in these bicyclic skeletons is due to their enormous potential for biological activity, since they are identical to those found in some isolated natural compounds found in Annonaceae family plants. These compounds belong to a group of molecules known as styryl lactones, whose members, in its great majority, present significant cytotoxicity against human tumor cells. The proposed sequence can open new alternatives for the preparation of unknown analogous of this series, always exploring the possibility of carbon chain extention through a Wittig reaction in the lactone carbonyl group. These new analogues must also be submitted to some antiproliferative essays. The present studies allow confirming that the transformation quinic acid to furanefurone saturated systems is feasible. From 1, it was not possible the preparation of the unsaturated furanefurone 2, but the proposed sequence for 3, 4 and 5 has shown new possibilities for the synthesis of other derivatives. / Mestrado / Quimica Organica / Mestre em Química

The Streptomyces metabolite 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC), the antheminones and the carvotacetone derivatives are all bioactive natural products, whose structure is based on the α oxymethyl-a,β-cyclohexenone moiety. Both COTC and antheminone A have been shown to exhibit cytotoxic and cancerostatic activity with low toxicity. The potent biological activity of these natural products has instigated numerous investigations into the synthesis of novel analogues in an attempt to determine the key structural features necessary for optimum bioactivity. The synthesis of a small library of novel anti-tumour agents which are structurally related to the natural products COTC and antheminone A is described, using the chiral pool material (-)-quinic acid as a starting material. At the outset, the aim of this project was to develop and optimise copper-mediated conjugate addition reactions and rhodium catalysed conjugate addition reactions of organoboron reagents to functionalised cyclic enones and subsequently, to apply the methodologies to the synthesis of the novel analogues. A range of novel mono-hydroxylated analogues bearing aryl side chains were prepared and their antiproliferative activity was assessed towards the A549 non-small cell cancer cell line. The biological assays revealed important structure-activity relationships and the most bioactive compound of this series had an IC50 value of 1.2 µM. In addition, the design and synthesis of a new class of GSH-activated prodrugs is described. These novel compounds are activated by GSH leading to intracellular release of an NQO1 inhibitor. The most potent compound of this new class of compounds had an IC50 value of 710 nm.

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