Síntese e avaliação da atividade antitumoral e antiprotozoária de 6-cantinonas contendo unidades arilideno-carboidrazida e alquil-carboxamida na posição-2

• Ano de defesa: 2012
• Autor(a) principal: Silva, Camila Mareco Bento Leite
• 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: Cantinonas; Síntese orgânica; Benzocantinonas; Atividade antitumoral; Atividade antileishmania; Atividade antitripanossômica; Brasil.; Ciências Exatas e da Terra; Química
• Link de acesso: http://repositorio.uem.br:8080/jspui/handle/1/3906

The canthin-6-ones are characterized as a subclass of β-carboline alkaloids, with an additional D-ring. This class of compounds displayed important pharmacological activities, such as, antifungal antibacterial, trypanocide, leishmanicide, anti-ulcer, anti-inflammatory and antitumor. The most of the reports on pharmacological activity of canthin-6-ones refer to their derivatives isolated from natural products. A few works on the synthesis and structure-activity relationship studies of this class of compounds are described. The importance of search for new antitumor, anti-trypanosoma and anti-leishmania agents, associated with biological activities reported for canthin-6-ones, led us to study of this class of compounds. Previous studies of our research group have shown that β-carbolines containing N-alkylcarboxamide and benzylidenocarbohydrazide groups in position-3, presented significant anti-trypanosoma, anti-leishmania and antitumor activities. In this work we have developed a synthesis and evaluation of antitumor, anti-trypanosoma and anti-leishmania activities of a series of benzo[4.5]canthin-6-ones containing the N-alkylcarboxamide and N-arylidenocarboxamide groups at C-2. For the preparation of proposed derivatives we employed the 2-benzo-carbomethoxy [4.5] canthin-6-one (3a) as synthetic intermediate, which was obtained from the condensation reaction of methyl ester L-tryptophan with phthalic anhydride, to afford the amide 37, followed by a 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU). The treatment of 3a with hydrazine hydrate originated the benzo[4.5]canthin-6-one-2-carbohydrazides (39), which by reaction with different aromatic aldehydes resulted in the of N-arylideno-benzo[4.5]canthin-6-one-2-carbohydrazides (40 a-f). To obtain the N-alkyl-benzo[4.5]canthin-6-one-carboxamides (43 a-g), the compound 3a was transformed to its acid chloride (42), which by a nucleophilic substitution reaction with different primary or secondary amines, resulted in their corresponding N-alkylcarboxamides The structures of the compounds synthesized were confirmed on the basis of their IR, 1H NMR and 13C NMR/DEPT and two-dimensional NMR techniques (COSY, HMQC) data. The compounds synthesized were evaluated for their antitumor activity against human cancer cells lines of glioma (U251), ovarian resistant (NCI-ADR/RES), mama (MCF-7), ovarian (OVCAR-03) and colon (HT29). The assays results showed that the compounds of N-arylidene-benzo[4.5]cantin-6- one -2 - carbohydrazides series (40-f) were inactive against all cancer cells lines evaluated, with IC50 > 100 µM. From the series of N-alkyl-benzo[4.5]canthin-6-one-carboxamides, the compound 43c, containing the piperazyl group at position-2, showed potent antitumor activity, with IC50 values in the range of 1.15 to 8.46 µM, against all cancer cell lines, showing potent activity for ovarian cancer cell lines (OVCAR-3) with IC50 of 1.15 µM. Also, the synthesized compounds were evaluated against epimastigote forms of Trypanosoma cruzi and promastigote forms of Leishmania amazonensis. The compounds of the N-arylideno-benzo[4.5]canthin-6-one-2- carbohydrazides (40-f) series were inactive against T. cruzi and L. amazonensis, with IC50 > 100 µM. For the series of N-alkyl-benzo[4.5]canthin-6-one-carboxamides 43a-g, the compounds 43c and 43e containing the piperazyl and morpholyl groups at C-2, showed potent activity against T. cruzi, with IC50 of 0.40 and 16.70 µM, respectively. In the assays against promastigote forms of Leishmania amazonensis, compounds 43c and 43e, demonstrated activity, with IC50 values of 0.896 and 14.87 µ M, respectively.