Biokoniugaty aza-BODIPY z biotyną w celowanej PDT. Synteza i właściwości fizykochemiczne.

Nowe barwniki aza-BODIPY są obecnie syntezowane i szczegółowo badane, aby znaleźć nowe potencjalne zastosowanie biochemiczne, medyczne czy przemysłowe. W niniejszej pracy dyplomowej, nowy fotosensybilizator bazujący na strukturze tetraarylo aza-BODIPY został zsyntetyzowany i zbadano jego właściwości fizykochemiczne. Rozważany fotouczulacz z grupy aza-BODIPY wykazuje efektywną absorpcję światła w zakresie okna terapeutycznego i, dzięki efektowi ciężkiego atomu, skutecznie generuje tlen singletowy. Ponadto, podjęto próbę otrzymania biokoniugatu aza-BODIPY z biotyną poprzez sprzęganie Sonogashiry. Sprzęganie to miało na celu zwiększenie powinowactwa związku to komórki rakowej. Wyznaczono molowy współczynnik absorpcji oraz wydajność kwantową tworzenia tlenu singletowego dla rozważanego fotosensybilizatora i porównano otrzymane wyniki z popularnymi fotouczulaczami używanymi obecnie w PDT. Wynikiem badań było otrzymanie nowego i efektywnego fotouczulacza.Novel aza-BODIPY dyes are synthesized and carefully examined nowadays for a new potential biochemical, medical and industrial applications. In this work, a new photosensitizer based on tetraaryl aza-BODIPY framework has been synthesized and its physicochemical properties have been studied. The studied aza-BODIPY photosensitizer exhibits efficient absorption of light in the therapeutic window and, via heavy atom effect, efficiently generates singlet oxygen. Moreover, an attempt has been made to obtain a bioconjugate of the aza-BODIPY and biotin molecule via Sonogashira coupling. This coupling was supposed to increase compound to tumor affinity. Molar extinction coefficient and singlet oxygen quantum yield were determined for the photosensitizer under question and compared with known and already used in PDT popular photosensitizers. In summary, as a result of this work, a novel and efficient photosensitizer has been obtained

Rapid study of organic reactions in flow systems

Continuous flow processing has become a frequent and invaluable tool in chemistry laboratories, thanks to unique control over reaction parameters, confinement of the reaction space allowing for the execution of hazardous chemistry and increasing the process safety, incorporation of modern analytical techniques for reaction monitoring, and ability to fully automate studied processes. All these aspects allowed for flow chemistry to make a significant impact within the domain of organic chemistry, especially in the field of process investigation and optimisation where various methodologies utilising unique aspects of continuous processing have been developed. The first presented methodology is for the investigation of solvent mixtures effects in organic reactions. A gradient of solvent composition is generated with time during a working flow experiment and in situ reaction monitoring affords information on reaction outcome against a full range of studied solvent mixture composition. The methodology was developed utilising model nucleophilic substitution reaction and then applied to imine formation reaction, where binary and ternary solvent mixtures have been investigated showing interesting non-linear results. The second technique developed allows for rapid investigation of process functional group compatibility and additive effects, presented in the example of solid phase catalysed click reaction. In such, the molecule containing investigated functional group or the additive is injected as a plug into a working stream of organic reaction, with simultaneous monitoring of the reaction mixture. The developed methodology allows for the determination of process compatibility with various organic moieties, and the nature of additive effect as well its reversibleness in a single flow experiment. A robust and versatile protocol for the synthesis of 1-monosubstituted and 1,4-disubstituted 1,2,3-triazoles in flow using copper-on-charcoal as a heterogeneous catalyst is presented. The methodology delivered a diverse set of substituted 1,2,3-triazoles with good functional group tolerance and high yields. Moreover, 2-ynoic acids were used as small-chain alkyne donors in a decarboxylation/cycloaddition cascade, allowing highly hazardous gaseous reagents to be bypassed. Finally, the flow platform was used for validation of the Switch-Off method and analysis of the optimisation experiments. The methodology relies on switching off the light source during the working photochemical flow transformation and monitoring the reaction composition as it leaves the photoreactor. Thus, the effect of all irradiation times up to a maximum can be analysed in a single flow experiment

Projektowanie, synteza i badanie aktywności chiralnych kompleksów tytanu jako katalizatorów do enancjoselektywnych reakcji Henry'ego i aza-Henry'ego.

Celem wykonanych badań było zbadanie aktywności chiralnych kompleksów tytanu(IV) bazujących na ligandach pół-salenowych do enancjoselektywnych reakcji Henry'ego i aza-Henry'ego. W pierwszym etapie badań, zaprojektowano i zsyntetyzowano chiralne ligandy pół-salenowe z prostych i komercyjnie dostępnych reagentów, przykładowo aldehydu salicylowego i aminoli otrzymanych z aminokwasów, a następnie przeprowadzono testy ich aktywności i stereoselektywności w wybranych reakcjach. Wykonane badania pokazały, iż produkty badanych reakcji tworzone są z umiarkowaną wydajnością (13% do 34%) i średnią diastereoselektywnością (1,6:1 do 4,26:1 dr) i enancjoselektywnością (7,0% do 74,5%). W przeprowadzonych badaniach zanalizowano również wpływ wielkości podstawnika estrowego oraz wielkości łańcucha bocznego nitrozwiązku na wyniki reakcji aza-Henry'ego. Ponadto, przeprowadzono badania nad możliwością zastąpienia tytanu(IV) w kompleksie przez inny metal, uzyskując zaskakujące wyniki badanych reakcji (30% do 35% wydajności, 1,24:1 do 31:1 dr oraz 2,9% do 74,3% ee). Uzyskane w toku badań wyniki mogą posłużyć jako dobry punkt wyjściowy do dalszych badań w dziedzinie katalizy asymetrycznej z wykorzystaniem kompleksów typu pół-salenowego.The aim of the research was to study the activity of chiral complexes based on semi-salen ligands with titanium(IV) metallic center in the asymmetric aza-Henry and Henry reactions. In the first stage of the studies, chiral semi-salen ligands were designed and synthesized from simple, commercially available reagents, i.e. salicylaldehyde and amino acid derived aminols, followed by tests of their activity and stereoselectivity in selected reactions. Research has shown that the products of the studied reactions form in relatively moderate yields (13% to 34%) and medium diastereoselectivities (1.6:1 to 4.26:1 dr) and enantioselectivities (7.0% to 74.5% ee). In conducted studies, the influence of the size of the ester substituent and the size of the nitro compound side chain on the results of the aza-Henry reaction was investigated. In addition, the possibility of substituting the metallic center in catalyst with metals other than titanium(IV) was examined, obtaining remarkable results of the studied reaction (30% to 35% yield, 1.24:1 to 31:1 dr and 26.9% to 74.3% ee). The acquired results open up a wide range of possible future research in the area of asymmetric catalysis with semi-salen type complexes

A Practical Flow Synthesis of 1,2,3-Triazoles

A robust and versatile protocol for synthesis of 1-monosubstituted and 1,4-disubstituted 1H-1,2,3-triazoles was established under continuous flow conditions using copper-on-charcoal as a heterogeneous catalyst. This methodology allowed for the synthesis of a diverse set of substituted 1,2,3-triazoles with good functional group tolerance and high yields. 2-Ynoic acids were also used as small-chain alkyne donors in a decarboxylation/cycloaddition cascade, allowing gaseous reagents to be bypassed, delivering desired triazoles in high yields. The developed methodology was used to synthesize an antiepileptic agent, rufinamide, which was obtained in 96% isolated yield

Rapid investigation of the effect of binary and ternary solvent gradient mixtures on reaction outcomes using a continuous flow system

In a continuous flow process, generating a gradient of solvent composition with time and monitoring of the reaction mixture as it leaves the reactor allows for rapid generation of reaction information against a full range of solvent mixture compositions. The methodology was developed by screening binary solvent mixtures in a SNAr reaction in which previously reported effects were efficiently reproduced. Binary and ternary solvent gradients were then applied to an imine forming reaction revealing interesting non-linear effects.</p

The switch-off method: rapid investigation of flow photochemical reactions

In a flow photochemical process switching off the light source and monitoring the reaction composition as it leaves the photoreactor allows the effect of all irradiation times up to a maximum to be analysed in a single experiment. The switch-off method was illustrated using three reactions: [2 + 2] intermolecular photocycloadditions between an alkene and alkyne, and between two alkenes, and a Mallory photocyclization of cis-stilbene

2-Sulfonylpyrimidines: Reactivity Adjustable Agents for Cysteine Arylation

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have systematically evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective and metal free cysteine S-arylation. 2-sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity with model tripeptide glutathione in vitro, covering 9 orders of magnitude. We achieved extremely fast chemo- and regio- specific arylation of a mutant p53 protein, and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure-reactivity relationship to date on heteroaryl sulfones, and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery

Structure–reactivity studies of 2-sulfonylpyrimidines allow selective protein arylation

Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering &gt;9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure–reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery