Síntese De Novos 1,2,3-Triazóis Inspirados No Srpin340 E Avaliação De Seus Efeitos Em Linhagem Celular De Glioblastoma Humano

Abstract

SYNTHESIS OF NOVEL 1,2,3-TRIAZOLES INSPIRED ON THE SRPIN340 AND EVALUATION OF THEIR EFFECTS ON HUMAN GLIOBLASTOMA CELL LINE. It is herein described the synthesis of a series of thirty novel 1,2,3-triazole1,4-disubstituted compounds inspired on the known SRPKs inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (SRPIN340) and biological evaluation of them against human glioblastoma multiforme cell line U87MG. Starting with 1-fluoro2-nitro-4- (trifluoromethyl)benzene (1), the substances were prepared via a five-step synthetic route. The crucial step corresponded to the copper-catalyzed cycloaddition reaction between trifluoromethyl phenyl azides and different alkynes. In general, the compounds were obtained with good yields and they were characterized utilizing spectroscopic (IR and NMR) and spectrometric (HRMS) techniques. The evaluation of the synthesized compounds at three different treatment time (24 h, 48 h, and 72 h) and concentrations (50, 100, and 150 µmol L-1) revealed that five derivatives were capable of reducing cell viability by 50% after 72 h of treatment at the highest concentration. On the contrary, three derivatives significantly increased cell viability being this effect more pronounced after 48 h of treatment. In this regard, it stands out the compound 2-((1-(2-morpholino-5-(trifluoromethyl)phenyl)-1H-1,2,3-triazol4-yl)methyl)isoindoline-1,3-dione (7) which increased cell viability in approximately 300% after 48 h of treatment at 100 µmol L-1. The substances that increased cell viaiblity present as common structural features the presence of a saturated nitrogen-containing six-membered ring and carbonylated fragments.

Screening of synthetic 1,2,3-triazolic compounds inspired by SRPIN340 as anti-Trypanosoma cruzi agents

“…Extending our analysis to other compounds examined by Sousa et al 34 , namely 6B to 6K (identified by Sousa et al. 34 as compounds 8 to 17), we found that these compounds did not substantially affect cellular growth of the U87MG lineage. This discrepancy in cytotoxicity can be primarily attributed to the choice of cell lineage, with U87MG cells representing human glioblastoma cells and L929 cells representing mouse fibroblasts.…”

“…The impact on cell viability varied when these compounds were applied to different cellular lineages and disease models. Notably, the cytotoxicity observed for compound 6A on L929 cells differed from its effect on the U87MG lineage, where there was no perceived cytotoxicity and cellular viability even showed an increase 34 . Extending our analysis to other compounds examined by Sousa et al 34 , namely 6B to 6K (identified by Sousa et al.…”

“…Notably, the cytotoxicity observed for compound 6A on L929 cells differed from its effect on the U87MG lineage, where there was no perceived cytotoxicity and cellular viability even showed an increase 34 . Extending our analysis to other compounds examined by Sousa et al 34 , namely 6B to 6K (identified by Sousa et al. 34 as compounds 8 to 17), we found that these compounds did not substantially affect cellular growth of the U87MG lineage.…”

“…Considering the relevance of azoles in the pursuit of new active drugs against CD, this study evaluated the in vitro and in vivo anti- T. cruzi activity of 11 synthetic 1,2,3-triazole compounds inspired by the kinase inhibitor SRPIN340, which inhibits glioblastoma proliferation in vitro 34 .…”

Efeito do inibidor de serine arginine protein kinases (SRPKS) SRPIN340 e derivados em células murinas de câncer de mama metastático

“…Esses achados estão de acordo com os de outros estudos, onde compostos sintetizados inspirados no SRPIN340 também mostraram citotoxicidade significativa contra células de glioblastoma, melanoma e leucemia (MOREIRA et al, 2018;SOUSA et al, 2021;SIQUEIRA et al, 2017). Essa maior citotoxicidade dos compostos análogos a SRPIN340 pode ter relação com a já relatada baixa potência de SRPIN340, conforme vista em estudos anteriores (GAMMONS et al, 2014;SIQUEIRA et al, 2020).…”