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Thesis (MSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Please refer to full text for abstract

Epilepsy is a neurological disease that affects approximately 50 million people worldwide and is related to oxidative stress, which plays an important role in the neuronal damage induced by seizures. The current drugs used in the treatment of this disease have their use often limited due to their adverse effects; moreover, approximately 30% of epileptic patients who are receiving drug treatment are not totally free of seizures. These facts motivated the development of this work that aims to synthesize, characterize and evaluate palladium(II) complexes derived from diazepam in order to obtain complexes that can be used to treat epilepsy. In this work were synthesized five complexes of diazepam-palladium(II): two in dimeric form (DIAZPdOAcD and DIAZPdClD) and three in monomeric form (DIAZPdOAcPPh3, DIAZPdClPPh3 and DIAZPdClPy). All these complexes were characterized by spectrometric techniques and elemental analysis; the monomer DIAZPdOAcD had your chemical structure elucidated by X-ray diffraction. In addition, all complexes were evaluated for anticonvulsant and antioxidante activities and for citotoxicity. Through the characterization techniques used in this work it was possible to confirm the formation of all the complexes; it is important to noted that the X-ray diffraction study of DIAZPdOAcD showed the distorted square-planar geometry of palladium(II), the occurrence of cyclopalladation and the open-book shape of this dimer. Regarding the anticonvulsant and antioxidante activities, it was observed that only the DIAZPdOAcD dimer presented significant results. With respect to cytotoxicity, all complexes showed more pronounced toxicity when compared to diazepam. However, the anticonvulsive effect and the potential neuroprotective effect performed by DIAZPdOAcD should be emphasized, since they are important characteristics of new drugs for the treatment of epilepsy. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A epilepsia é uma doença neurológica que afeta aproximadamente 50 milhões de pessoas em todo o mundo e está relacionada ao estresse oxidativo, que desempenha um importante papel no dano neuronal induzido por convulsões. Os fármacos atuais utilizados no tratamento desta doença apresentam seu uso frequentemente limitado devido aos seus efeitos adversos; além disso, aproximadamente 30% dos pacientes epiléticos que estão recebendo tratamento medicamentoso não ficam totalmente livres de convulsões. Tais fatos motivaram o desenvolvimento deste trabalho que apresenta como objetivo sintetizar, caracterizar e avaliar complexos de paládio(II) derivados do diazepam com a finalidade de obter complexos que possam ser utilizados para o tratamento da epilepsia. Neste trabalho foram sintetizados cinco complexos de paládio(II) derivados do diazepam: dois na forma dimérica (DIAZPdOAcD e DIAZPdClD) e três na forma monomérica (DIAZPdOAcPPh3, DIAZPdClPPh3, e DIAZPdClPy). Todos esses complexos foram caracterizados por técnicas espectrométricas e análise elementar; e o dímero DIAZPdOAcD teve sua estrutura química elucidada através de difração de raios X. Além disso, todos os complexos foram avaliados quanto às atividades anticonvulsivante e antioxidante e à citotoxicidade. Através das técnicas de caracterização utilizadas neste trabalho foi possível confirmar a formação de todos os complexos; cabe destacar que por meio do estudo de difração de raios X do DIAZPdOAcD observou-se a geometria quadrada plana distorcida do paládio(II), a ocorrência da ciclopaladação e a forma de livro aberto deste dímero. Com relação às atividades anticonvulsivante e antioxidante, observou-se que somente o dímero DIAZPdOAcD apresentou resultados significativos. No que se refere à citotoxicidade, todos os complexos apresentaram uma maior toxicidade quando comparados ao diazepam. No entanto, cabe salientar o efeito anticonvulsivante e o potencial efeito neuroprotetor desempenhados pelo DIAZPdOAcD, pois são características importantes de novos fármacos para o tratamento da epilepsia.

Im ersten Teil der Arbeit wird die Synthese neopentyl- und neosilylsubstituierter Phosphane zur Verwendung als Liganden in katalytisch aktiven Palladiumkomplexen beschrieben. Die Aktivität wurde in der Suzuki-Miyaura Kreuzkupplungsreaktion getestet. Während die neosilylsubstituierten Phosphane 2:1 Addukte (5b und 5d) mit geeigneten Palladiumsalzen bilden, welche moderate Katalyseaktivität zeigen, untergehen die neopentylsubstituierten Komplexe schnelle Cyclometalierungsreaktionen in Gegenwart von Basen und bilden die katalytisch wenig aktiven Palladacyclen (6a, 6e, and 6g). Die deaktivierende Cylometallierung konnte durch Darstellung der Palladiumcomplexe ausgehend von Pd(cod)Cl2 in Abwesenheit von Basen vermieden werden. Die erhaltenen 2:1 Phosphaneaddukte zeigten deutlich verbesserte Aktivität. Daraus wurde geschlossen, dass die Cyclomettalierung als Nebenreaktion eine wichtige Deaktiverungsmöglichkeit darstellt, diese Überlegung veranlasste uns Trialkylphosphane mittlerer Größe, mit Substituenten die nur schwer eine Cyclometallierungen eingehen können zu testen. Die Verwendung der Phosphoniumsalze 4h (R = Cy, R‘ = neopentyl) und 4m (R = iPr, R‘ = CH2Cy) führt zu höheren Aktivitäten in der Suzuki-Miyaura Kreuzkupplung, als bestes Katalysatorsystem hat sich die Kombination aus Pd2(dba)3 oder Pd(OAc)2 und entsprechendem Phosphoniumsalz ergeben. Im zweiten Teil dieser Arbeit werden Synthesen zu neuen biphenylbasierten Diphosphanen (70, 71, 76, and 77) vorgestellt. Die Palladiumkomplexe wurden ebenfalls auf ihre Eignung als Katalysatoren in palladiumkatalysierten Suzuki-Miyaura Kreuzkupplungen getestet und zeigen für diese Klasse von Komplexen gute Aktivität. Das Tetraphosphan 82 wurde für die Synthese des zweikernigen Palladium(II)-komplex 83 eingesetzt. Durch die Koordination des D2h-symmetrischen Tetraphosphanes an die Palladiumatome wird die Symmetrie des Moleküls erniedrigt und folglich erhält man den formal D2-symmetrischen Komplex 83. / In the first part of this thesis, the synthesis and catalytic activity of neopentyl and neosilyl substituted phosphine palladium complexes is described. The complexes have been tested in the Suzuki-Miyaura cross-coupling reaction. Whereas the neosilyl substituted phosphines form 2:1 adducts (5b and 5d) with Palladium salts which showed moderate activity, the neopentyl complexes quickly undergo cyclometallation in presence of bases to form Palladacycles (6a, 6e, and 6g) which showed only moderate catalytic activity. Cyclometallation could be avoided by the preparation starting from Pd(cod)Cl2 in the absence of bases. The obtained 2:1 phosphine adducts showed superior activity. We concluded that cyclometallation process is an important deactivation pathway, this prompted us to test trialkyl phosphine ligands with medium size but substituents not reliable to cyclometallation. We have been pleased to find that 4h (R = Cy, R‘ = neopentyl) and 4m (R = iPr, R‘ = CH2Cy) showed good activity in the Suzuki-Miyaura cross-coupling reaction. The best results have been obtained by in situ preparation of active catalyst from Pd2(dba)3 or Pd(OAc)2 and the appropriate phosphonium salt. In the second part of this thesis, the first synthesis of a new family of biphenyl based bisphosphine ligands (70, 71, 76, and 77) has been reported. Their palladium complexes were successfully tested as catalyst in the Suzuki cross-coupling reaction. Within the class of bisphosphine based palladium complexes they show good activity in Suzuki-Miyaura cross-coupling reaction. Systematically, was expanded our synthesis strategy and we were able to introduce the first synthesis of a highly symmetric 2,2',6,6'-tetraphosphinobiphenyl. Tetraphosphine 82 was used as ligand in a dinuclear palladium(II) complex 83. Upon complexation the D2h symmetric 2,2’,6,6’-tetraphosphine lead to a chiral D2 symmetric complex 83.

Im ersten Teil der Arbeit wird die Synthese neopentyl- und neosilylsubstituierter Phosphane zur Verwendung als Liganden in katalytisch aktiven Palladiumkomplexen beschrieben. Die Aktivität wurde in der Suzuki-Miyaura Kreuzkupplungsreaktion getestet. Während die neosilylsubstituierten Phosphane 2:1 Addukte (5b und 5d) mit geeigneten Palladiumsalzen bilden, welche moderate Katalyseaktivität zeigen, untergehen die neopentylsubstituierten Komplexe schnelle Cyclometalierungsreaktionen in Gegenwart von Basen und bilden die katalytisch wenig aktiven Palladacyclen (6a, 6e, and 6g). Die deaktivierende Cylometallierung konnte durch Darstellung der Palladiumcomplexe ausgehend von Pd(cod)Cl2 in Abwesenheit von Basen vermieden werden. Die erhaltenen 2:1 Phosphaneaddukte zeigten deutlich verbesserte Aktivität. Daraus wurde geschlossen, dass die Cyclomettalierung als Nebenreaktion eine wichtige Deaktiverungsmöglichkeit darstellt, diese Überlegung veranlasste uns Trialkylphosphane mittlerer Größe, mit Substituenten die nur schwer eine Cyclometallierungen eingehen können zu testen. Die Verwendung der Phosphoniumsalze 4h (R = Cy, R‘ = neopentyl) und 4m (R = iPr, R‘ = CH2Cy) führt zu höheren Aktivitäten in der Suzuki-Miyaura Kreuzkupplung, als bestes Katalysatorsystem hat sich die Kombination aus Pd2(dba)3 oder Pd(OAc)2 und entsprechendem Phosphoniumsalz ergeben. Im zweiten Teil dieser Arbeit werden Synthesen zu neuen biphenylbasierten Diphosphanen (70, 71, 76, and 77) vorgestellt. Die Palladiumkomplexe wurden ebenfalls auf ihre Eignung als Katalysatoren in palladiumkatalysierten Suzuki-Miyaura Kreuzkupplungen getestet und zeigen für diese Klasse von Komplexen gute Aktivität. Das Tetraphosphan 82 wurde für die Synthese des zweikernigen Palladium(II)-komplex 83 eingesetzt. Durch die Koordination des D2h-symmetrischen Tetraphosphanes an die Palladiumatome wird die Symmetrie des Moleküls erniedrigt und folglich erhält man den formal D2-symmetrischen Komplex 83. / In the first part of this thesis, the synthesis and catalytic activity of neopentyl and neosilyl substituted phosphine palladium complexes is described. The complexes have been tested in the Suzuki-Miyaura cross-coupling reaction. Whereas the neosilyl substituted phosphines form 2:1 adducts (5b and 5d) with Palladium salts which showed moderate activity, the neopentyl complexes quickly undergo cyclometallation in presence of bases to form Palladacycles (6a, 6e, and 6g) which showed only moderate catalytic activity. Cyclometallation could be avoided by the preparation starting from Pd(cod)Cl2 in the absence of bases. The obtained 2:1 phosphine adducts showed superior activity. We concluded that cyclometallation process is an important deactivation pathway, this prompted us to test trialkyl phosphine ligands with medium size but substituents not reliable to cyclometallation. We have been pleased to find that 4h (R = Cy, R‘ = neopentyl) and 4m (R = iPr, R‘ = CH2Cy) showed good activity in the Suzuki-Miyaura cross-coupling reaction. The best results have been obtained by in situ preparation of active catalyst from Pd2(dba)3 or Pd(OAc)2 and the appropriate phosphonium salt. In the second part of this thesis, the first synthesis of a new family of biphenyl based bisphosphine ligands (70, 71, 76, and 77) has been reported. Their palladium complexes were successfully tested as catalyst in the Suzuki cross-coupling reaction. Within the class of bisphosphine based palladium complexes they show good activity in Suzuki-Miyaura cross-coupling reaction. Systematically, was expanded our synthesis strategy and we were able to introduce the first synthesis of a highly symmetric 2,2',6,6'-tetraphosphinobiphenyl. Tetraphosphine 82 was used as ligand in a dinuclear palladium(II) complex 83. Upon complexation the D2h symmetric 2,2’,6,6’-tetraphosphine lead to a chiral D2 symmetric complex 83.