RESUMEN
The successful application of fragment-based drug discovery strategy for the efficient synthesis of phenoxy- or phenylamino-2-phenyl-benzofuran, -benzoxazole and -benzothiazole quinones is described. Interestingly, in the final step of the synthesis of the target compounds, unusual results were observed on the regiochemistry of the reaction of bromoquinones with phenol and aniline. A theoretical study was carried out for better understanding the factors that control the regiochemistry of these reactions. The substituted heterocyclic quinones were evaluated inâ vitro to determine their cytotoxicity by the MTT method in three pancreatic cancer cell lines (MIA-PaCa-2, BxPC-3, and AsPC-1). Phenoxy benzothiazole quinone 26a showed potent cytotoxic activity against BxPC-3â cell lines, while phenylamino benzoxazole quinone 20 was the most potent on MIA-PaCa-2 cells. Finally, electrochemical properties of these quinones were determined to correlate with a potential mechanism of action. All these results, indicate that the phenoxy quinone fragment led to compounds with increased activity against pancreatic cancer cells.
Asunto(s)
Antineoplásicos , Neoplasias Pancreáticas , Antineoplásicos/química , Benzotiazoles/química , Línea Celular Tumoral , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Quinonas/química , Quinonas/farmacología , Neoplasias PancreáticasRESUMEN
The piperidine alkaloid composition from young stems of Lobelia polyphylla Hook & Arn. was determined by gas chromatography mass spectrometry (GC-MS). The tentative structures, without the stereochemistry, were obtained by the analysis of the fragmentation patterns of the mass spectra of each compound. The stems contained a mixture of lobeline (1), norlobelanidine (2), 1-(1-(2-hydroxy-2-phenylethyl)-1-methylpiperidin) butane-2-ol (3), 8-propyl-10-phenyl lobelionol (4), 1-(6-(2-hydroxy-2-phenylethyl)-1-methylpiperidin) butane-2-one (5), 1-(6-(2-hidroxypentyl)-1-ethylpiperidin) butane-2-one (6) and 1-methyl-2-piperidinemethanol (7). The role of these alkaloids in the toxic, narcotic and hallucinogenic effects, produced after smoking the aerial parts of this species is discussed.
La composición de alcaloides piperidínicos de tallos jóvenes de Lobelia polyphylla Hook & Arn. se determinó por cromatografía de gases acoplada a espectrometría de masas (CG-EM). Las estructuras tentativas sin incluir la estereoquímica, se obtuvieron mediante el análisis de los patrones de fragmentación de los espectros de masas de cada compuesto. Los tallos contienen una mezcla de lobelina (1), norlobelanidina (2), 1-(1-(2-hidroxi-2-feniletil)-1-metilpiperidin) butano-2-ol (3), 8-propil-10-fenil lobelionol (4), 1-(6-(2-hidroxi-2-feniletil)-1-metilpiperidin) butano-2-ona (5), 1-(6-(2-hidroxypentyl)-1-etilpiperidin) butano-2-ona (6) y 1-metil-2-piperidinmetanol (7). Se discute el posible papel de estos alcaloides en los efectos tóxicos, estupefacientes y alucinógenos, producidos después de haber fumado la parte aérea de esta especie.
