SwePub
Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "AMNE:(MEDICIN OCH HÄLSOVETENSKAP Medicinska grundvetenskaper Läkemedelskemi) ;pers:(Larhed Mats Professor)"

Sökning: AMNE:(MEDICIN OCH HÄLSOVETENSKAP Medicinska grundvetenskaper Läkemedelskemi) > Larhed Mats Professor

  • Resultat 1-10 av 15
Sortera/gruppera träfflistan
   
NumreringReferensOmslagsbildHitta
1.
  • Öhrngren, Per (författare)
  • Tertiary Alcohol- or β-Hydroxy γ-Lactam-Based HIV-1 Protease Inhibitors : Microwave Applications in Batch and Continuous Flow Organic Synthesis
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Since the outbreak of the HIV/AIDS pandemic in the 1980s, the disease has cost the lives of over 30 million people, and a further 33 million are currently living with the HIV infection. With the appropriate treatment, HIV/AIDS can today be regarded as a chronic but manageable disease. However, treatment is not available globally and UNAIDS still estimates that there are currently 5000 AIDS-related deaths worldwide per day. HIV protease inhibitors (PIs) constitute one of the fundaments of HIV treatment, and are commonly used in so-called highly active antiretroviral therapy (HAART), together with reverse transcriptase inhibitors. Although there are ten PIs on the market, there is still a need for novel structures. The rapid development of resistant strains, due to the high frequency of mutations, together with the commonly observed adverse effects of the drugs available, illustrate the need to develop new potent structures. Two novel scaffolds were investigated in this work. A tertiary alcohol-containing scaffold comprising a three-carbon tether, and a β-hydroxy γ-lactam-based scaffold were designed, synthesized and evaluated using enzyme- and cell-based assays. X-ray analyses of inhibitors from each class provided information on inhibitor–protease interactions. The inhibitors containing the tertiary alcohol provided at best an enzymatic inhibition (Ki) of 2.3 nM, and an inhibition in the cell-based assay (EC50) of 0.17 µM. The γ-lactam-based inhibitors exhibited better inhibition than the first series; the best values being Ki = 0.7 nM and EC50 = 0.04 µM. The second part of these studies involved the evaluation of a novel non-resonance continuous-flow microwave instrument. The instrument was validated regarding heating capacity, temperature stability and temperature homogeneity. A number of model reactions were performed with low- and high-microwave-absorbing solvents. It was found that the microwave heating source allowed rapid temperature adjustment, together with easily regulated, flow-dependent reaction times, providing an efficient tool for reaction optimisation.
  •  
2.
  • Orrling, Kristina M., 1976- (författare)
  • On the Versatility of Microwave-Assisted Chemistry : Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Today, the demand for speed in drug discovery is constantly increasing, particularly in the iterative processes of hit validation and expansion and lead optimization. Irradiation with microwaves (MWs) has been applied in the area of organic synthesis to accelerate chemical reactions and to facilitate the generation of new chemical entities since 1986. In the work presented in this thesis, the use of MW-mediated heating has been expanded to address three fields of drug discovery, namely hit expansion, chemical library generation and genomics. In the first project, potential inhibitors of malaria aspartic proteases were designed and synthesized, partly by MW-assisted organic chemistry, and evaluated with regard to their inhibitory efficacy on five malaria aspartic proteases and their selectivity over two human aspartic proteases. The synthetic work included the development of fast and convenient methods of MW-assisted formation of thiazolidines and epoxy esters. Some of the resulting structures proved to be efficacious inhibitors of the aspartic protease that degrades haemoglobin in all four malaria parasites infecting man. No inhibitor affected the human aspartic proteases. Expedient, two-step, single-operation synthetic routes to heterocycles of medicinal interest were developed in the second and third projects. In the former, the use of a versatile synthon, Ph3PCCO, provided α,β-unsaturated lactones, lactams and amides within 5–10 minutes. In the latter project, saturated lactams were formed from amines and lactones in 35 minutes, in the absence of strong additives. These two MW-mediated protocols allowed the reduction of the reaction time from several hours or days to minutes. In the fourth project, a fully automated MW-assisted protocol for the important enzyme-catalysed polymerase chain reaction (PCR) was established. In addition, the PCR reaction could be performed in unusually large volumes, 2.5 mL and 15 mL, with yields corresponding to those from conventional PCR. Good amplification rates suggested that the thermophilic enzyme, Taq polymerase, was not affected by the MW radiation.
  •  
3.
  • Axelsson, Linda, 1977- (författare)
  • Development of HIV-1 Protease Inhibitors and Palladium-Catalyzed Synthesis of Aryl Ketones and N-Allylbenzamides
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The use of palladium-catalyzed reactions to introduce new carbon-carbon bonds is a fundamental synthetic strategy that has been widely embraced due to its high chemo- and regioselectivity and functional group tolerance. In this context, Pd(0)-catalyzed aminocarbonylations using Mo(CO)6 instead of toxic and gaseous CO and with allylamine as the nucleophile were investigated. The aminocarbonylated product dominated over the Mizoroki-Heck product, and (hetero)aryl iodides, bromides and chlorides gave N-allylbenzamides in good yields.In this thesis improvements to an existing protocol for the Pd(II)-catalyzed synthesis of aryl ketones from five benzoic acids and a variety of nitriles are also presented. Addition of TFA improved the yields and employing THF as solvent enabled the use of solid nitriles, and the aryl ketones were isolated in good yields.The pandemic of HIV infection is one of the greatest public health issues of our time and approximately 35.3 million people worldwide are living with HIV. There are currently many drugs on the market targeting various parts of the viral reproduction cycle, but the problems of resistance warrant the search for new drugs. HIV-1 protease makes the virus mature into infectious particles. In this thesis a new type of HIV-1 protease inhibitor (PI) is presented, based on two of the PIs on the market, atazanavir and indinavir, but it has a tertiary alcohol, as well as a two-carbon tether between the quaternary carbon and the hydrazide β-nitrogen. A total of 25 new inhibitors were designed, synthesized and biologically evaluated, the best compound had an EC50 value of 3 nM.Based on this series a project aimed at synthesizing macrocycles spanning the P1-P3 area was initiated. Macrocycles often tend to have an improved affinity and metabolic profile compared to their linear analogs. Introduction of a handle in the para position of the P1 benzyl group proved difficult, despite efforts to synthesize intermediates containing either a bromo-, hydroxy-, methoxy-, silyl-group protected hydroxy- or an alkyne-group. The lactone intermediate was abandoned in favor of an alternative synthetic route and initial studies were found to be promising. This new approach requires further investigation before the target macrocycles can be synthesized. 
  •  
4.
  • Engen, Karin, 1988- (författare)
  • Inhibitors Targeting Insulin-Regulated Aminopeptidase (IRAP) : Identification, Synthesis and Evaluation
  • 2020
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Insulin-regulated aminopeptidase (IRAP) has emerged as a potential new therapeutic target for treatment of cognitive disorders. Inhibition of the enzymatic activity facilitates cognition in rodents. Potent and selective peptide and pseudopeptide based inhibitors have been developed, but most of them suffer from poor pharmacokinetics and blood-brain-barrier penetration. Hence, development of less-complex inhibitors with good pharmacokinetic properties are of great importance.The aim of this thesis was to identify and optimize new small-molecule based IRAP inhibitors for use as research tools to investigate the cognitive effects of IRAP inhibition. Adaptation of an existing enzymatic assay into a screening compatible procedure allowed the evaluation of 10,500 compounds as IRAP inhibitors. The screening campaign resulted in 23 compounds displaying more than 60% inhibition. Two of these compounds, a spiro-oxindole dihydroquinazolinone and an imidazo[1,5-α]pyridine, were further investigated in terms of structure-activity relationship, physicochemical properties, metabolic stability, and mechanism of inhibition.Spiro-oxindole dihydroquinazolinone based IRAP inhibitors were synthesized via fast and simple microwave-promoted reactions, either in batch or in a continuous flow approach. The most potent compounds displayed sub-µM affinity, and interestingly an uncompetitive mode of inhibition with the synthetic substrate used in the assay. Molecular modeling confirmed the possibility of simultaneous binding of the compounds and the substrate. Furthermore, the molecular modeling suggested that the S-enantiomer accounts for the inhibitory effect observed with this compound series. The compounds also proved inactive on the closely related enzyme aminopeptidase N. Unfortunately, the spiro-oxindole based inhibitors suffered from poor solubility and metabolic stability.Imidazo[1,5-α]pyridine based IRAP inhibitors were synthesized via a five step procedure, providing inhibitors in the low-µM range. The stereospecificity of a methyl group proved important for inhibition. The compound series displayed no inhibitory activity on aminopeptidase N. Intriguing, these compounds exhibit a noncompetitive inhibition mechanism with the model substrate. As observed for the spiro-compounds, the imidazopyridines suffered from both poor solubility and metabolic stability.  In summary, the work presented in this thesis provide synthetic procedures, initial structure-activity relationship, and pharmacological evaluation of two distinct inhibitors classes. The compounds are among the first non-peptidic IRAP inhibitors presented, serving as interesting starting points in the development of research tools for use in models of cognition.
  •  
5.
  • Isaksson, Rebecka, 1988- (författare)
  • Ligands of the Angiotensin II Type 2 Receptor : Exploring structure and function of the AT2R ligand C38
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The renin-angiotensin-aldosterone-system (RAAS) control blood-pressure regulation, exerted by the main effector peptide angiotensin II (AngII) binding the angiotensin II type 1 receptor (AT1R). While hypertension is the most known disease caused by over-activity in RAAS, several proteins in the system exhibit protective functions.One of these protective proteins is the GPCR angiotensin II type 2 receptor (AT2R). After decades of research its biological role remain to be fully elucidated, exemplified by the two AT2R ligands currently in clinical trials; agonist C21 for treatment of idiopathic pulmonary fibrosis, and antagonist EMA401 for treatment of peripheral neuropathic pain. Making a minor structural change in C21 shifted the pharmacological profile, generating the regioisomer antagonist C38. The renewed interest in AT2R antagonists as potential drugs to treat neuropathic pain make continued studies of antagonist C38 highly interesting. The aim of this thesis was to continue exploring the structure-activity relationship of antagonist C38 by investigating three chemical motifs to identify compounds with better drug-like properties. Developing a new chemical method, transesterification of sulfonyl carbamates, allowed quick modification of one of the motifs. Reducing the length of the sulfonyl carbamate chain significantly increased metabolic stability in liver microsomes without losing affinity for AT2R. Using a model substrate, the transesterification reaction was applied in a microwave heated continuous-flow system.Adding small substituents to the central phenyl ring generated a second library of ligands with retained affinity, but with no observed increase in metabolic stability. Docking studies with this library and a recently presented crystal structure of AT2R, resulted in a proposed binding mode of C38. Replacing the imidazole head group with bicyclic amides slightly improved affinity. While metabolic stability improved compared to previously published amide analogs, the bicyclic ligands were inferior to C38. Developing an assay based on RAW264.7 macrophages allowed a new evaluation of the functional activity exhibited by C38. In contrast to previous research, C21 and C38 both display agonistic functional activity in the macrophage assay.In summary, the work presented in this thesis expand the structure-activity relationship of C38 and its pharmacological profile. Two new ligands were identified that could serve as tools in murine models of neuropathic pain.
  •  
6.
  • Lagerlund, Olof (författare)
  • Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Tuberculosis (TB) is a major infectious disease, killing about 2 million people annually throughout the world. Today's TB treatment is a lengthy procedure involving a combination of antibiotics. No new TB drug has been introduced onto the market in the past 40 years, and the emergence of multi- and extensively drug-resistant TB calls for new drugs. Finding new drug targets is important and one such target is the Mycobacterium tuberculosis enzyme glutamine synthetase (GS), which catalyses the formation of glutamine from glutamic acid. In this work, novel GS inhibitors and new Pd(0)-catalyzed methods have been developed. A microwave-enhanced Pd(0)-catalyzed α-arylation reaction was developed using water as solvent, and a phenylglycine scaffold was identified using structure-based design. A series of α-arylated phenylglycine derivates was produced at moderate to good yields. Some of these were biologically evaluated against GS. A novel scaffold, 3-amino-imidazo[1,2-a]pyridine, was identified by high-throughput screening directed towards GS. This type of compound could be easily produced via a Ugi-type, microwave-promoted multi-component reaction in 20 min. The scaffold was investigated by changing one substituent at a time, and in an experimental design where 8 factors were varied in the same design. Several potent inhibitors were identified; amongst them the most potent inhibitor to date (IC50 = 0.38 µM). Two discrete structure-activity relationships were established, and one of the inhibitors was co-crystallized. The first general aminocarbonylation of aryl chlorides and the first aminocarbonylation of alkenyl phosphates were developed. Alkenyl chlorides, bromides and triflates were investigated in the same transformation utilizing Mo(CO)6 as a solid carbon monoxide source. Two different Pd(0)-based catalytic systems were developed. A wide variety of aryl chlorides and amines could be transformed into the corresponding amides with good yields. The alkenyl substrates produced low to good yields.
  •  
7.
  • Lindh, Jonas, 1977- (författare)
  • Palladium(II)-Catalyzed Coupling Reactions
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Sustainable chemical processes are becoming increasingly important in all fields of synthetic chemistry. Catalysis can play an important role in developing environmentally benign chemical processes, and transition metals have an important role to play in the area of green chemistry. In particular, palladium(II) catalysis includes many key features for successful green chemistry methods, as demonstrated by a number of eco-friendly oxidation reactions catalyzed by palladium(II). The aim of the work presented in this thesis was to develop novel and greener palladium(II)-catalyzed coupling reactions. In striving to achieve this aim, the first open-vessel, room-temperature palladium(II)-catalyzed oxidative Heck reaction, using oxygen from the air as the reoxidant of palladium, was developed. In a further investigation of the palladium(II)-catalyzed oxidative Heck reaction, base-free conditions for the transformation were identified and suitable conditions for microwave-assisted oxidative Heck reactions were established. A convenient and low-cost palladium(II)-catalyzed method for the synthesis of styrene derivatives, by coupling arylboranes with vinyl acetate, was developed. The reaction mechanism was studied using ESI-MS, which enabled the detection of cationic palladium intermediates in ongoing productive reactions, and a plausible catalytic cycle was proposed. In an attempt to make the oxidative Heck and the styrene synthesis reactions more attractive from an industrial point of view, conditions for continuous flow synthesis were identified. The results were generally good and rapid synthesis of the desired products was obtained. The first palladium(II)-catalyzed C–P bond-forming Hirao-type reaction, employing arylboranes instead of the commonly used aryl halides, was developed. An ESI-MS study was performed, and a plausible catalytic pathway was suggested. Finally, a novel method for synthesizing aryl ketones from benzoic acids and nitriles, via palladium(II)-catalyzed decarboxylation of the benzoic acids, was established. Further, the reaction mechanism was studied by ESI-MS and a plausible catalytic route presented.
  •  
8.
  • Lindman, Jens, 1990- (författare)
  • Palladium(0)-Catalyzed Spirocyclization and Carbonylation Reactions : Ligands Targeting the Angiotensin II Type 2 Receptor
  • 2023
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Palladium(0)-catalyzed chemistry represents one of the most important methods for the construction of carbon-carbon bonds, which are ubiquitous in organic compounds. The first part of this thesis describes the palladium(0)-catalyzed diastereoselective Mizoroki-Heck reaction of Vince lactam-derived precursors for the formation of spiroindolines (paper I) and spirooxindoles, which are scaffolds present in several natural products with interesting biological activity. The scope of the spiroindoline synthesis was investigated by varying the substitution on the cyclopentenyl-tethered aniline spirocyclization precursor. The mechanistic reasons behind the high diastereoselectivity of the spirocyclization reaction was also investigated through density functional theory (DFT) calculations. Functionalization of the N-terminal amino acid of therapeutic peptides is a strategy that has been employed for the improvement of metabolic stability. In paper II, a palladium(0)-catalyzed carbonylation method employing ex situ carbon monoxide generation from Mo(CO)6 in a two-chamber system is used for the N-capping of amino acids using various aryl bromides and triflates. The second part of the thesis describes the synthesis and biological evaluation of angiotensin II type 2 receptor (AT2R) ligands. The AT2R is a G-protein coupled receptor belonging to the renin-angiotensin-aldosterone system (RAAS), which is most commonly associated with the hypertensive disorder caused by an exaggerated activation of the angiotensin II type 1 receptor (AT1R). However, activation of AT2R exerts different and sometimes completely opposing effects to AT1R and has been implicated in processes related to neuropathic pain, where the AT2R antagonist EMA401 has been in clinical trials for this indication. In papers III and IV, the AT2R antagonist C38 developed in our laboratory, is used as a model compound for the synthesis of analogs with the aim of expanding our knowledge regarding the structure-activity relationship of the C38 scaffold. Three general strategies were used; functionalization of the C38 phenyl ring, replacement of the benzyl imidazole of C38 with bicyclic amides and extension of the linker between the phenyl ring and imidazole by the inclusion of a carbonyl. Through these approaches, compounds with improved affinity towards AT2R and increased metabolic stability were identified, which might serve as tools for the continued study of the AT2R.
  •  
9.
  • Nordqvist, Anneli, 1978- (författare)
  • Hit Identification and Hit Expansion in Antituberculosis Drug Discovery : Design and Synthesis of Glutamine Synthetase and 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase Inhibitors
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Since the discovery of Mycobacterium tuberculosis (Mtb) as the bacterial agent causing tuberculosis, the permanent eradication of this disease has proven challenging. Although a number of drugs exist for the treatment of tuberculosis, 1.7 million people still die every year from this infection. The current treatment regimen involves lengthy combination therapy with four different drugs in an effort to combat the development of resistance. However, multidrug-resistant and extensively drug-resistant strains are emerging in all parts of the world. Therefore, new drugs effective in the treatment of tuberculosis are much-needed. The work presented in this thesis was focused on the early stages of drug discovery by applying different hit identification and hit expansion strategies in the exploration of two new potential drug targets, glutamine synthetase (GS) and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR). A literature survey was first carried out to identify new Mtb GS inhibitors from compounds known to inhibit GS in other species. Three compounds, structurally unrelated to the typical amino acid derivatives of previously known GS inhibitors, were then discovered by virtual screening and found to be Mtb GS inhibitors, exhibiting activities in the millimolar range. Imidazo[1,2-a]pyridine analogues were also investigated as Mtb GS inhibitors. The chemical functionality, size requirements and position of the substituents in the imidazo[1,2-a]pyridine hit were investigated, and a chemical library was designed based on a focused hierarchical design of experiments approach. The X-ray structure of one of the inhibitors in complex with Mtb GS provided additional insight into the structure–activity relationships of this class of compounds. Finally, new α-arylated fosmidomycin analogues were synthesized as inhibitors of Mtb DXR, exhibiting IC50 values down to 0.8 µM. This work shows that a wide variety of aryl groups are tolerated by the enzyme. Cinnamaldehydes are important synthetic intermediates in the synthesis of fosmidomycin analogues. These were prepared by an oxidative Heck reaction from acrolein and various arylboronic acids. Electron-rich, electron-poor, heterocyclic and sterically hindered boronic acids could be employed, furnishing cinnamaldehydes in 43–92% yield.
  •  
10.
  • Wångsell, Fredrik, 1978- (författare)
  • Design and Synthesis of Aspartic and Serine Protease Inhibitors : Targeting the BACE-1 and the HCV NS3 Protease
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This thesis describes work done to design and synthesize protease inhibitors, with the intention of developing therapeutic agents for Alzheimer’s disease (AD) and the chronic liver condition caused by infection of the hepatitis C virus (HCV). AD is the most common form of dementia, and HCV infection is the primary reason for liver transplantation in industrialized countries. Today, these two illnesses affect 24 and 170 million people, respectively. It has been shown that the human aspartic protease BACE-1 plays an important role in the development of AD, and thus inhibition of BACE-1 may offer a way to improve the quality of life of individuals afflicted with the disease. Furthermore, it is known that the serine protease NS3 is a vital component in the replication of HCV. Several novel potent BACE-1 inhibitors encompassing different transition state mimics were prepared. First, a hydroxyethylene moiety encompassing a secondary hydroxyl group was evaluated as a transition state analogue, producing inhibitors in the low nanomolar range. Various tertiary hydroxyl isosteres were also investigated as the central core, with the aim of shielding the pivotal hydroxyl group. These transition state isosteres consisted of tertiary hydroxyl analogues of previously used secondary hydroxyl containing norstatine, statine, and hydroxyethylamine isosteres. Several tertiary hydroxyl-containing inhibitors were found to be active in the low micromolar range. In addition, two inhibitors were co-crystallized with the BACE-1 enzyme to provide X-ray crystal structures, which furnished valuable binding information for further design of improved BACE-1 inhibitors. The goal in the HCV NS3 protease inhibitor project was to design, synthesize and evaluate a novel hydroxycyclopentene bioisostere to the previously used acyl-hydroxyproline moiety. The investigation revealed that it was possible to synthesize inhibitors containing this new bioisostere that were potent in the low nanomolar range. Further optimization by rigidification of the most active inhibitor resulted in equipotent macrocyclic compounds.
  •  
Skapa referenser, mejla, bekava och länka
  • Resultat 1-10 av 15

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy