Síntese E Avaliação Da Atividade Citotóxica De Derivados Do Eugenol Contendo Núcleos 1,2,3-Triazólicos

Abstract

SYNTHESIS AND CYTOTOXIC ACTIVITY OF 1,2,3-TRIAZOLE DERIVATIVES OF EUGENOL. Eugenol is an aromatic compound found in several plant species. It presents important biological activities including cytotoxicity. In this paper, it is described the synthesis and the evaluation of the cytotoxic activity of eugenol derivatives bearing 1,2,3-triazole functionalities. Eugenol, extracted via hydrodistillation from dried flower buds of Eugenia caryophyllata (=Syzygium aromaticum), was submitted to alkylation reactions to afford two terminal alkynes in good yields. The key reaction involved in the preparation of eugenol derivatives corresponded to the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC), between alkynylated eugenol derivatives and different benzyl azides. The evaluation of the cytotoxicity of twenty seven synthesized derivatives against HL60 leukemia cell line revealed that at 100 µmol L -1 , five of them, namely 4-((4-allyl-2-methoxyphenoxy)methyl)-1-(3-bromobenzyl)-1H-1,2,3-triazole (6n), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-benzyl-1H-1,2,3-triazole (7a), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-chlorobenzyl)-1H-1,2,3-triazole (7c), 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(4-iodobenzyl)-1H-1,2,3-triazole (7e) and 4-(3-(4-allyl-2-methoxyphenoxy)propyl)-1-(3-bromobenzyl)-1H-1,2,3-triazole (7m), were capable of significantly decreasing cell viability. These most active triazolic derivatives were also evaluated against B16F10 melanoma and Nalm6 leukemia cell lines. While only compound 7a was active against the former, compounds 6n, 7a, and 7m displayed activity against the latter. Derivative 7a was active against all cell lines. It is believed that eugenol derivatives bearing triazole functionalities may represent a scaffold to be explored toward the development of new agents against cancer.Keywords: eugenol; triazole; cytotoxic activity; click chemistry; CuAAC reaction. INTRODUÇÃOO câncer correspondeu a uma das principais causas de mortes no século XX e vem difundindo-se de forma contínua e aumentando sua incidência no século XXI.1 Sua denominação está associada a um conjunto de mais de 100 doenças que têm em comum o crescimento desordenado (maligno) de células anormais que invadem os tecidos e órgãos, podendo espalhar-se (metástase) para outras regiões do corpo. Devido à rápida divisão celular, estas células podem se tornar muito agressivas e incontroláveis, determinando assim a formação de tumores ou neoplasias malignas.De acordo com a Organização Mundial da Saúde (OMS), o câncer é um problema de saúde pública, principalmente em países em desenvolvimento. A estimativa para o ano de 2025 aponta para a ocorrência de aproximadamente 20 milhões de novos casos. Investigações científicas multidisciplinares têm sido conduzidas buscando encontrar alternativas para combater esta doença, no entanto, a cura ainda não foi alcançada. Os principais tipos de tratamento empregados para o câncer baseiam-se, de forma geral, na associação da ressecção cirúrgica dos tumores ao tratamento radioterápico e a quimioterapi...