Síntese e avaliação da atividade antitumoral e antiprotozoária de derivados 1-substituído-ß-carbolínicos contendo grupos imido-carboxamida na posição-3

• Ano de defesa: 2012
• Autor(a) principal: Panice, Manuela Ribeiro
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Estadual de Maringá; Brasil; Departamento de Química; Programa de Pós-Graduação em Química; UEM; Maringá, PR; Centro de Ciências Exatas
• Palavras-chave em Português: Síntese de alcalóides; Atividade antitumoral; Atividade antileishmania; Atividade antitripanossoma; Ciências Exatas e da Terra; Química
• Link de acesso: http://repositorio.uem.br:8080/jspui/handle/1/3908

Synthetic and naturally occurring ß-carboline alkaloids present a large spectrum of pharmacological properties, including antimicrobial, antitrypanosomal, antileishmanial, antiviral and antitumor activities. Structure-activity relationships studies have demonstrated that presence of appropriated substituents, mainly at positions-1 and -3 of ß-carboline nucleus led to compounds with higher activity. Due to potential of these alkaloids, our research group has been developing works focusing on the synthesis, evaluation of pharmacological activity and structure-activity relationship studies of 1,3-disubstituted-ß-carbolines. In order to obtain compounds with higher activity, in the present work we carried out the synthesis and antitumor, antitrypanosomal and antileishmanial activity evaluation of a series of 1-substituted β-carboline derivatives containing the N- (1,3-dioxo-1,3- diidroisoindol-2-yl), N-(2,5-dioxo-2,5-diidropirrol-2-yl) and N-(2,5-dioxo-pirrolidin-1-yl)- carboxamide groups at position-3. Compounds containing phthalimide, maleimide and succinimide belong to the class of imides and can be isolated from natural products or be obtained synthetically. These compounds present several pharmacological activities, such as anticonvulsant, analgesic, anti-inflammatory, antifungal, antibacterial, insecticidal and antispasmodic. For preparation of the proposed derivatives, the ß-carbolines-3-carboidrazidas 58(ah) were used as key intermediates. These intermediates were obtained from the esterification of L-tryptophan 54 with methanol and sulfuric acid, followed by Pictet-Spengler condensation of L-tryptophan methyl ester 55 with aromatic aldehydes containing electronwithdrawing or donating groups to provide the 1,2,3,4-tetrahydro-β-carbolines 56(a-h). The aromatization of 56(a-h) with sulfur, in xylene, followed by the treatment of ß-carbolines 57(a-h) with hydrazine hydrate, in ethanol, provided 58(a-h). The synthesis of β-carboline-3-N-(1,3-dioxo-1.3-diidroisoindol-2-yl)-carboxamides 59(a-h) was performed by the reaction of 58(a-h) with phthalic anhydride, in xylene. The β-carboline-3-N-(2,5-dioxo-2,5-diidropirrol-2-yl)-carboxamides 60(a,b,d,e) were obtained by the reaction of 58(a,b,d,e,f,h) with maleic anhydride, sodium acetate, in acetic acid. Compounds containing the N-(2,5-dioxo-pirrolidin-1-yl)-carboxamide 61(a,b,d-g) were obtained by the reaction of 58(a,b, d-g) with succinic anhydride in toluene, with the use of p-toluenesulphonic acid as catalyst. The compounds synthesized were characterized by the analysis of their IR, 1H NMR and 13C/DEPT, including two-dimensional NMR techniques of COSY and HSQC, spectroscopic data. The synthesized compounds were evaluated for their antitumor activity against human tumor cell lines of glioma (U251), breast cancer (MCF-7), ovary resistant (NCIADR/RES), kidney (786-0), lung (NCI-H460), prostate (PC-3), ovary (OVCAR-03), colon (HT29), HaCaT (human keratinocyte). These compounds were also evaluated against epimastigote forms of Trypanosoma cruzi and promastigote forms of Leishmania amazonensis. The bioassay results pointed compounds with significant antitumor, antitrypanosomal and antileishmanial activities, mainly for those β-carboline derivatives containing the group N-(2,5-dioxo-2,5-diidropirrol-2-yl)-carboxamide in position-3.