Síntese de tetrahidroquinolinas a partir da D-eritrose

Dissertação de mestrado em Química Medicinal

Síntese de novas tieno[3,2-b]piridinas com potencial atividade biológica contendo 1,2,3-triazoles 1,4-dissubstituídos obtidos por reação "click" de ciclioadição azida-alquino catalisada por Cu(I)-CuAAC

Dissertação de mestrado em Química Medicinal

Síntese e caracterização de nanopartículas vetorizadas para células tumorais com possível aplicação na entrega controlada de fármacos

Dissertação de mestrado em Química Medicinal

Mecanismes de reacció de sistemes catalítics amb èmfasi en carbens de Fischer i quantificació de l'aromaticitat en petites molècules inorgàniques cícliques i planes.

El tema principal del treball és sobre l'estudi teòric de l'estructura i reactivitat en carbens de Fischer de la forma (CO)5Cr=C(X)R (X= OH, NH2, OMe, NMe2 i R= CHCH2 i Ph). Particularment, el nostre interès va sorgir del tipus de reaccions de cicloadicció que donen lloc a la síntesi de productes naturals i fàrmacs de gran valor afegit. Hem estudiat els mecanismes de reacció dels casos més comuns de cicloanul•lació: la reacció de benzanul•lació de Dötz i ciclopentanulacions que es troben en competència amb el primer cas, derivats de l'inserció de acetilè i fenilacetilè. En l'últim pas de les reaccions que comporten la formació d'un sistema de més d'un anell, hi tenim una migració del complex metàl•lic de crom d'un extrem a un altre anomenat com rearranjament haptotròpic. Aleshores, hem investigat sobre els mecanismes de migració haptotròpica de Cr(CO)3 sobre hidrocarburs aromàtics policíclics analitzant l'efecte de la mida i la curvatura del sistema així com la complexació d'un segon fragment metàl•lic a la manera de coordinació als anells. D'una altre banda, vam estudiar l'aromaticitat en 54 cúmuls cíclics de molecules inorgàniques mitjançant metodologia desenvolupada al nostre grup de recerca i altres. Vam proposar la tècnica del scan-NICS com nova mesura quantitativa d'aromaticitat i reportar l'escassa correlació entre els distints índexs d'aromaticitat a la literatura. Finalment, com resultat de col•laboracions en estades de recerca, he desenvolupat propostes de mecanismes de reacció en sistemes catalítics de isonitrils i fosfinetà-amides i en dímers de gassos nobles.

Benzodiazepine receptor ligand influences on learning: an endogenous modulatory mechanism mediated by benzodiazepines possibly of alimentary origin

In rats pre-but not post-training ip administration of either flumazenil, a central benzodiazepine (BSD) receptor antagonist, or of n-butyl-B-carboline-carboxylate (BCCB), an inverse agonist, enhanced retention of inhibitory avoidance learning. Flumazenil vlocked the enhancing effect of BCCB, and the inhibitory effect of the BZD agonists clonazepam and diazepam also given pre-training. Post-training administration of these drugs had no effects. The peripheral BZD receptor agonist/chloride channel blocker Ro5-4864 had no effect on the inhibitory avoidance task when given ip prior to training, buth it caused enhancement when given immediately post-training either ip or icv. This effect was blocked by PK11195, a competitive antagonist of Ro5-4864. These results suggest that ther is an endogenous mechanism mediated by BZD agonists, which is sensitive to inverse agonists and that normally down-regulates the formation of memories through a mechanism involving GABA-A receptors and the corresponding chloride channels. The most likely agonists for the endogenous mechanism suggested are the diazepam-like BZDs found in brain whose origin is possibly alimentary. Levels of these BZDs in the cortex were found to sharply decrease after inhibitory acoidance training or mere exposure to the training apparatus.

Síntesi estereoselectiva d'anàlegs ciclobutènics d'L-nucleòsids

En els darrers 30 anys, els anàlegs de nucleòsids han estat una part essencial de la teràpia antiviral. Més recentment, els anàlegs carbocíclics de nucleòsids s'han convertit en importants objectius pel desenvolupament de nous agents terapèutics antivirals i antitumorals, en tant que l'absència de l'enllaç N-glicosídic els confereix una major estabilitat davant l'acció de les fosforilases. Per altra banda, s'ha descrit que alguns nucleòsids de configuració L presenten, en alguns casos, una bona activitat antiviral, una major estabilitat metabòlica i una toxicitat inferior a la dels seus homòlegs de configuració natural. El present treball planteja la síntesi estereoselectiva de derivats ciclobutènics de L-nucleòsids com a agents terapèutics, susceptibles de presentar una major activitat antiviral i una menor toxicitat que els agents actuals. Per assolir aquest objectiu, s'ha construït l'anell ciclobutènic mitjançant una reacció de fotocicloaddició [2+2]. Al mateix temps, s'ha desenvolupat un estudi de la influència del dissolvent en la reacció de fotocicloaddició [2+2] d'enones a alquens halogenats. A més, s'han estudiat diverses condicions de treball per dur a terme la reacció de deshalogenació dels derivats clorats preparats amb la metodologia anterior, utilitzant Zn com a reductor i amb un sistema d'escalfament per microones com a substituent dels mètodes d'escalfament convencionals. Aquest estudi ha permès disminuir notablement el temps d'aquesta reacció, passant de 7 hores a 20 minuts. Les condicions òptimes d'ambdues reaccions determinades amb aquests estudis han permès preparar l'intermedi clau per a la introducció de les bases nitrogenades, essent aquest un potencial precursor dels anàlegs ciclobutènics de nucleòsids, així com sintetitzar el primer producte de la ruta sintètica dissenyada que presenta la base nitrogenada a la seva estructura.

Synthesis and in vitro evaluation of a novel radioligand for αvβ3 integrin receptor imaging: [(18)F]FPPA-c(RGDfK).

The development of RGD-based antagonist of αvβ3 integrin receptor has enhanced the interest in PET probes to image this receptor for the early detection of cancer, to monitor the disease progression and the response to therapy. In this work, a novel prosthetic group (N-(4-fluorophenyl)pent-4-ynamide or FPPA) for the (18)F-labeling of an αvβ3 selective RGD-peptide was successfully prepared. [(18)F]FPPA was obtained in three steps with a radiochemical yield of 44% (decay corrected). Conjugation to c(RGDfK(N3)) by the Cu(II) catalyzed Huisgen azido alkyne cycloaddition provided the [(18)F]FPPA-c(RGDfK) with a radiochemical yield of 29% (decay corrected), in an overall synthesis time of 140min.

Charge dependent substrate activity of C3' and N3 functionalized, organometallic technetium and rhenium-labeled thymidine derivatives toward human thymidine kinase 1.

Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for the noninvasive imaging of cancer cell proliferation using radiolabeled thymidine analogues such as [(18)F]3'-fluoro-3'-deoxythymidine ([(18)F]FLT). A thymidine analogue for single photon emission computed tomography (SPECT), which incorporates the readily available and inexpensive nuclide technetium-99m, would be of considerable practical interest. hTK1 is known to accommodate modification of the structure of the natural substrate thymidine at the positions N3 and C3' and, to a lesser extent, C5. In this work, we used the copper-catalyzed azide-alkyne cycloaddition to synthesize two series of derivatives in which thymidine is functionalized at either the C3' or N3 position with chelating systems suitable for the M(CO)(3) core (M = (99m)Tc, Re). The click chemistry approach enabled complexes with different structures and overall charges to be synthesized from a common precursor. Using this strategy, the first organometallic hTK1 substrates in which thymidine is modified at the C3' position were identified. Phosphorylation of the organometallic derivatives was measured relative to thymidine. We have shown that the influence of the overall charge of the derivatives is dependent on the position of functionalization. In the case of the C3'-functionalized derivatives, neutral and anionic substrates were most readily phosphorylated (20-28% of the value for the parent ligand thymidine), whereas for the N3-functionalized derivatives, cationic and neutral complexes were apparently better substrates for the enzyme (14-18%) than anionic derivatives (9%).

Synthesis of a non-peptidic PET tracer designed for α5β1 integrin receptor.

Arginine-glycine-aspartic acid (RGD)-containing peptides have been traditionally used as PET probes to noninvasively image angiogenesis, but recently, small selective molecules for α5 β1 integrin receptor have been developed with promising results. Sixty-one antagonists were screened, and tert-butyl (S)-3-(2-((3R,5S)-1-(3-(1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)propanoyl)-5-((pyridin-2-ylamino)methyl)pyrrolidin-3-yloxy)acetamido)-2-(2,4,6-trimethylbenzamido)propanoate (FPMt) was selected for the development of a PET tracer to image the expression of α5 β1 integrin receptors. An alkynyl precursor (PMt) was initially synthesized in six steps, and its radiolabeling was performed according to the azide-alkyne copper(II)-catalyzed Huisgen's cycloaddition by using 1-azido-2-[(18)F]fluoroethane ([(18)F]12). Different reaction conditions between PMt and [(18)F]12 were investigated, but all of them afforded [(18)F]FPMt in 15 min with similar radiochemical yields (80-83%, decay corrected). Overall, the final radiopharmaceutical ([(18)F]FPMt) was obtained after a synthesis time of 60-70 min in 42-44% decay-corrected radiochemical yield.

Synthesis of F-18-labeled cyclic-[RGDfK] peptides for PET imaging of angiogenesis

Objectives: αvβ3 integrin is of great interest for tumor targeting because of its high concentration in tumor tissue. It recognizes ligands containing an arginine-glycine-aspartate motif (RGD), and a number of RGD-containing peptides have been developed as PET imaging probes of angiogenesis. We synthesized a series of 18F-labeled cyclic-[RGDfK] peptides for in vivo imaging of αvβ3 expression. Our F-18 labeled prosthetic groups were attached to the αvβ3 ligand via click chemistry, and the reaction conditions (time, temperature, solvent and pH) were optimized by using single modified amino acids.Methods: Seven amino acids were selected considering their different biochemical properties (polarity, total charge, presence of aromatic ring and heteroatom). All the amino acids were modified by the introduction of azido moiety to allow the interaction with alkyne prosthetic groups. Once the conditions of the click chemistry were optimized, the prosthetic groups were also coupled with the cyclic-[RGDfK] exhibiting an azido function. 4- Trimethylammonium-nitrobenzene triflate was used as precursor for the radiosynthesis of the prosthetic groups. The fluorination was carried out with K2CO3/K2.2.2 in CH3CN at 95 oC, and the nitro group was reduced with NaBH4 and Pd/C in MeOH. The resulting 18F-aniline was subsequently coupled to alkynoic acids to yield the final F-18 labeled prosthetic groups. Finally, the prosthetic groups were attached to the peptides via Huisgen's cycloaddition. Figure 1. F-18 labeled αvβ3 ligand.Results: Our new prosthetic groups were successfully clicked to the modified amino acids and to the cyclic- [RGDfK], and the reactions were almost quantitative within 1 to 3.5 h. The pH of the reaction did not influence the reaction kinetic and yield. The four steps of the F-18 labeling were completely automated providing the final products in quantities and yields practical for PET imaging. IC50 values of our ligands for αvβ3 and α5β1 demonstrated a high selectivity of our compounds towards αvβ3, as well as the negligible effect of the prosthetic groups on the affinity of the ligand to its receptor, as confirmed by the prediction of the molecular modeling.Conclusions: We have successfully synthesized novel F-18 labeled prosthetic groups, as well as novel PET imaging probes of αvβ3 expression. The reaction conditions of the Huisgen's cycloaddition were optimized with selected modified amino acids, and subsequently transposed to the cyclic-[RGDfK] peptide. IC50 data demonstrate that our 18F-labeled ligands were selective for αvβ3. In vivo microPET/CT studies in tumor bearing mice are underway.

Protected maleimide building blocks for the decoration of peptides, peptoids and peptide nucleic acids

Monomers allowing for the introduction of [2,5-dimethylfuran]-protected maleimides into polyamides such as peptides, peptide nucleic acids, and peptoids were prepared, as well as the corresponding oligomers. Suitable maleimide deprotection conditions were established in each case. The stability of the adducts generated by Michael-type maleimide-thiol reaction and Diels-Alder cycloaddition to maleimide deprotection conditions was exploited to prepare a variety of conjugates from peptide and PNA scaffolds incorporating one free and one protected maleimide. The target molecules were synthesized by using two subsequent maleimide-involving click reactions separated by a maleimide deprotection step. Carrying out maleimide deprotection and conjugation simultaneously gave better results than performing the two reactions subsequently.

Monte Carlo derivation of filtered tungsten anode X-ray spectra for dose computation in digital mammography

Abstract Objective: Derive filtered tungsten X-ray spectra used in digital mammography systems by means of Monte Carlo simulations. Materials and Methods: Filtered spectra for rhodium filter were obtained for tube potentials between 26 and 32 kV. The half-value layer (HVL) of simulated filtered spectra were compared with those obtained experimentally with a solid state detector Unfors model 8202031-H Xi R/F & MAM Detector Platinum and 8201023-C Xi Base unit Platinum Plus w mAs in a Hologic Selenia Dimensions system using a direct radiography mode. Results: Calculated HVL values showed good agreement as compared with those obtained experimentally. The greatest relative difference between the Monte Carlo calculated HVL values and experimental HVL values was 4%. Conclusion: The results show that the filtered tungsten anode X-ray spectra and the EGSnrc Monte Carlo code can be used for mean glandular dose determination in mammography.

Cicloadições [3+4] via cátions oxialílicos: aplicações em sínteses orgânicas

Several methodologies for the generation of oxyallyl cations from polybromoketones and other substrates are discussed. The mechanistic aspect of the [3+4] cycloaddition reaction between these cations and dienes leading to the formation of seven membered ring carbocyclic compounds is presented. Finally, some synthetic applications of the [3+4] cycloaddition are shown.

Utilização de α,α-Diclorociclobutanonas em Síntese de Produtos Naturais

The preparation and chemical potentiality of a,a-dichlorocyclobutanones as useful intermediates in the total synthesis of natural products are reviewed. Some aspects related to the recent advances reported in the literature about the mechanism of [2+2] cycloaddition reaction between dichloroketene and olefins are also presented.

Potencialidades da utilização de compostos de ródio na confecção de sensores eletroquímicos: uma breve revisão

The electrochemistry field has increased in recent years, specially in the search for new sensors to monitor specific analyte in complex samples. In order to improve electrodes, many rhodium compounds have been used as electron mediators for novel sensors development. The most used compounds for this purpose are metal, metal complexes and some organic dyes. Rhodium complexes are known by their good catalytic properties and it could be useful in the sensor field. However, there are only a few reports, on the use of rhodium complexes in sensors and biosensors. A brief review of the electrochemistry of rhodium complexes and some discription of their properties which make those compounds suitable for development of sensor and biosensor.