5-nitrofuraldehido darinių antimikrobinio aktyvumo tyrimas, toksiškumo, farmakokinetinių savybių ir struktūros aktyvumo ryšio įvertinimas. K. Gaivelytės magistro baigiamasis darbas. Moksliniai vadovai: dr. V. Petrikaitė, dr. J. Šarlauskas, prof. habil. dr. A. Pavilonis; Kauno medicinos universiteto, Farmacijos fakulteto, Vaistų chemijos katedra. Kaunas, 2010. Darbo tikslas – įvertinti 5-nitrofuraldehido darinių struktūros įtaką jų antimikrobiniam aktyvumui ir parinkti perspektyviausius antimikrobinius junginius tolimesniems tyrimams. Tyrimo metodai. Junginių antimikrobinio aktyvumo prognozė atlikta panaudojant PASS programą. Antimikrobinis aktyvumas ištirtas in vitro serijinio skiedimo standžioje terpėje metodu. Junginių farmakokinetinių savybių ir toksiškumo prognozė atlikta, panaudojant ADME/Tox Boxes programą. Tyrimo rezultatai. PASS programa antibakterinį ir priešgrybelinį aktyvumą prognozavo visiems tiriamiems junginiams. Atlikus tyrimus in vitro, nustatyta, kad junginių aktyvumas prieš įvairius mikroorganizmus skyrėsi, nitrofurano fragmento neturintys junginiai buvo visai neaktyvūs. Nitrofurano bisdariniai yra gana aktyvūs prieš visas bakterijas (MSK = 0,5 100 μg/ml), išskyrus P. aeruginosa, K. pneumoniae ir P. mirabilis. Bisjunginys BIC-34, turintis butilo fragmentą, buvo aktyviausias prieš S. aureus, E. faecalis ir B. subtilis, o piridino liekaną turintis bisjunginys BIC 67 – prieš K. pneumoniae, P. aeruginosa, P. mirabilis (MSK = 50 μg/ml). Gali būti, kad šio... [toliau žr. visą tekstą] / Analysis of 5-nitrofuraldehyde derivatives antimicrobial activity, evaluation of toxicity, pharmacokinetic properties and structure – activity relationship. K. Gaivelytė Master Thesis. Scientific supervisors: Dr. V. Petrikaitė, Dr. J. Šarlauskas, Prof. Habil. Dr. A. Pavilonis; Kaunas University of Medicine, Faculty of Pharmacy, Department of Medicinal Chemistry. Kaunas, 2010. The Aim of the Research – to evaluate the influence of the structure of 5-nitrofuraldehyde derivatives and identify the most promising compounds for the further research. Methods. Prognosis of antimicrobial activity of all compounds was carried out by using PASS software. Antimicrobial activity was tested in vitro by using a serial dilution in agar technique. Pharmacokinetic properties and toxicity were predicted by using ADME/Tox Boxes program. Results. PASS program predicted antibacterial and antifungal activity for all tested compounds. The results of experiments in vitro showed that activity against various microorganisms was different; compounds without nitrofuran fragment were not active. Biscompouds were active enough against all bacteria (MIC = 0,5-100 μg/ml), except P. aeruginosa, K. pneumoniae and P. mirabilis. Biscompoud possessing butyl fragment in its structure was the most active against S. aureus, E. faecalis and B. subtilis and biscompound BIC-67 with the moiety of pyridine was the most active against K. pneumoniae, P. aeruginosa, P. mirabilis (MIC = 50 μg/ml). It could be that the... [to full text]

Individuals with high levels of plasma triglycerides are at high risk to develop cardiovascular disease (CVD), currently one of the major causes of death worldwide. Recent epidemiological studies show that loss-of-function mutations in the APOC3 gene lower plasma triglyceride levels and reduce the incidence of coronary artery disease. The APOC3 gene encodes for apolipoprotein (APO) C3, known as an inhibitor of lipoprotein lipase (LPL) activity. Similarly, a common gain-of-function mutation in the LPL gene is associated with reduced risk for CVD. LPL is central for the metabolism of lipids in blood. The enzyme acts at the endothelial surface of the capillary bed where it hydrolyzes triglycerides in circulating triglyceride-rich lipoproteins (TRLs) and thereby allows uptake of fatty acids in adjacent tissues. LPL activity has to be rapidly modulated to adapt to the metabolic demands of different tissues. The current view is that LPL is constitutively expressed and that the rapid modulation of the enzymatic activity occurs by some different controller proteins. Angiopoietin-like protein 4 (ANGPTL4) is one of the main candidates for control of LPL activity. ANGPTL4 causes irreversible inactivation through dissociation of the active LPL dimer to inactive monomers. Other proteins that have effects on LPL activity are the APOCs which are surface components of the substrate TRLs. APOC2 is a well-known LPL co-factor, whereas APOC1 and APOC3 independently inhibit LPL activity. Given the important role of LPL for triglyceride homeostasis in blood, the aim of this thesis was to find small molecules that could increase LPL activity and serve as lead compounds in future drug discovery efforts. Another aim was to investigate the molecular mechanisms for how APOC1 and APOC3 inhibit LPL activity. Using a small molecule screening library we have identified small molecules that can protect LPL from inactivation by ANGPTL4 during incubations in vitro. Following a structure-activity relationship study we have synthesized lead compounds that more efficiently protect LPL from inactivation by ANGPTL4 in vitro and also have dramatic triglyceride-lowering properties in vivo. In a separate study we show that low concentrations of fatty acids possess the ability to prevent inactivation of LPL by ANGPTL4 under in vitro conditions. With regard to APOC1 and APOC3 we demonstrate that when bound to TRLs, these apolipoproteins prevent binding of LPL to the lipid/water interface. This results in decreased lipolysis and in an increased susceptibility of LPL to inactivation by ANGPTL4. We demonstrate that hydrophobic amino acid residues that are centrally located in the APOC3 molecule are critical for attachment of this protein to lipid emulsion particles and consequently for inhibition of LPL activity. In summary, this work has identified a lead compound that protects LPL from inactivation by ANGPTL4 in vitro and lowers triglycerides in vivo. In addition, we propose a molecular mechanism for inhibition of LPL activity by APOC1 and APOC3.

Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes. The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities. Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 7 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Thesis (Ph.D. in Neuroscience) -- University of Colorado at Denver and Health Sciences Center, 2006. / Typescript. Includes bibliographical references (leaves 108-118). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xvii, 271 p.; also includes graphics. Includes bibliographical references (p. 245-269). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 355-382).

Submitted by Jos? Henrique Henrique (jose.neves@ufvjm.edu.br) on 2017-09-20T20:31:49Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) gabriele_azevedo_cardoso.pdf: 4324631 bytes, checksum: 3efd70a64b9fe1de1234371d61299990 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2017-10-09T13:35:54Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) gabriele_azevedo_cardoso.pdf: 4324631 bytes, checksum: 3efd70a64b9fe1de1234371d61299990 (MD5) / Made available in DSpace on 2017-10-09T13:35:54Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) gabriele_azevedo_cardoso.pdf: 4324631 bytes, checksum: 3efd70a64b9fe1de1234371d61299990 (MD5) Previous issue date: 2017 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Funda??o de Amparo ? Pesquisa do Estado de Minas Gerais (FAPEMIG) / A necessidade de desenvolvimento de novos agentes antimicrobianos cresce ? medida que se torna maior a resist?ncia de microrganismos aos antibi?ticos usualmente empregados. Nesse sentido, os pept?deos antimicrobianos (PAMs) surgem como uma excelente alternativa para o desenvolvimento de novos antibi?ticos. O presente trabalho prop?s a s?ntese do pept?deo antimicrobiano LyeTx-I para estudos de mecanismo de a??o em membranas bacterianas, empregando diferentes t?cnicas biof?sicas e estruturais. O pept?deo LyeTx-I, composto por 24 res?duos de amino?cidos, foi isolado pela primeira vez do veneno de aracn?deos da esp?cie Lycosa erythrognata. Utilizando como t?cnicas principais a ITC e a RMN para obten??o de par?metros cin?ticos, termodin?micos e da intera??o pept?deo-membrana, foi poss?vel avaliar a rela??o estrutura e atividade do pept?deo LyeTx-I. Foram utilizadas ainda, t?cnicas complementares de CD, extravasamento de CF, fluoresc?ncia de Trp, DLS e, potencial zeta para obter informa??es adicionais acerca do modo de intera??o do pept?deo. Observou-se a predomin?ncia de conforma??o helicoidal do pept?deo LyeTx-I, tanto em meios biomim?ticos zwitteri?nicos, quanto em meios ani?nicos. Em meios ani?nicos, observou-se maior conte?do de ?-h?lice, bem como maior constante de intera??o, enquanto que em presen?a de ambientes zwitteri?nicas foram observadas menor helicidade e constante de intera??o. Os dados termodin?micos, obtidos para ambos os meios, mostraram que o processo de intera??o pept?deo-membrana ? dirigido principalmente pela componente entr?pica, uma vez que a componente ent?lpica ? menor. Os dados estruturais e termodin?micos foram coerentes com os demais estudos biof?sicos. Foi observada a partir da an?lise de extravasamento de CF maior capacidade de forma??o de poros no meio ani?nico. Os dados de fluoresc?ncia intr?nseca de Trp e de supress?o de fluoresc?ncia por acrilamida mostraram maior mudan?a de ambiente qu?mico para apolar, do res?duo de Trp-2, quando em presen?a de meio biomim?tico ani?nico. Dessa forma, o pept?deo apresenta maior capacidade de permeabilizar a membrana ani?nica. Al?m disso, o estudo comparativo entre os meios zwitteri?nicos e ani?nicos, permitiu verificar que, embora a intera??o eletrost?tica seja importante para a intera??o pept?deo-membrana, a permeabiliza??o do LyeTx-I na membrana fosfolip?dica ? fundamental para a lise celular. Dessa forma, este estudo mostra que o pept?deo LyeTx-I apresenta elevada prefer?ncia por intera??o com bicamadas fosfolip?dicas ani?nicas, o que faz dele um potencial agente bactericida. / Disserta??o (Mestrado) ? Programa de P?s-Gradua??o em Qu?mica, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2017. / The demand for the development of new antimicrobial agents increases in line with the resistance of microorganisms to the antibiotics usually employed. In this sense, antimicrobial peptides (AMPs) appear as an alternative to the classical antibiotics. The present work proposed the synthesis of the antimicrobial peptide LyeTx-I for studies of mechanism of action in bacterial membranes using a set of biophysical and structural techniques. LyeTx-I peptide is composed of 24 amino acid residues and was isolated for the first time from the venom of the Lycosa erythrognata arachnid species. In order to evaluate the structure-activity relationship of the LyeTx-I, we have employed ITC and NMR as main techniques to obtain the kinetic, thermodynamic and structural parameters of the peptide-membrane interaction. Complementary measurements of CD, CF extravasation, Trp fluorescence, DLS and zeta potential were also used as additional information about the mode of action of the peptide. The ?-helical conformation of the LyeTx-I peptide was observed either in presence of zwitterionic and anionic biomimetic media. Nevertheless, a higher ?-helix content and interaction constant was observed for LyeTx-I in all anionic media when compared to the zwitterionic environments. The thermodynamic data gathered in both media, showed that the peptide-membrane interaction is driven mainly by the entropic contributions, since the enthalpic component is smaller. The structural and thermodynamic data were consistent with the complementary biophysical experiments. It was observed from the CF extravasation a greater capacity of pore formation in the anionic medium. Intrinsic Trp fluorescence showed also a greater change of the residue of Trp-2 to the apolar chemical environment in the presence of anionic biomimetic medium. In this way, the peptide presents a higher capacity to permeabilize the anionic membrane. In addition, the comparative study between the zwitterionic and anionic media, reveals that, although the electrostatic interaction is important to the peptide-membrane interaction, the permeabilization of the LyeTx-I peptide in the phospholipid membrane is fundamental for the cellular lysis. Finally, the study clearly shows the high preference of LyeTx-I for interacting anionic phospholipid bilayers, which makes it a potential bactericidal agent.