RESUMEN
All stereoisomers of methoxybutane and fluorobutane type of 1,7-seco-2,7'-cyclolignane were synthesized and cytotoxic activities of these compounds were compared with those of all stereoisomers of butane and butanol type compounds. Both enantiomers of butane type secocyclolignane showed higher cytotoxic activity (IC50=16-20 µM) than methoxy type compounds, whereas none was observed for all the stereoisomers of butanol type secocyclolignane, however, (-)-Kadangustin J showed stereospecific cytotoxic activity (IC50=47-67 µM). Since (R)-9'-fluoro derivative 23 was most potent (IC50=19 µM) among the corresponding fluoro stereoisomers, (R)-9'-alkyl derivatives were synthesized, hydrophobic 9'-heptyl derivative 27 showing highest activity (IC50=3.7 µM against HL-60, IC50=3.1 µM against HeLa) in this experiment. Apoptosis induction caused by Caspase 3 and 9 for (R)-9'-heptyl derivative 27 was observed in the research on the mechanism. A degradation of DNA into small fragments was also shown by DNA ladder assay.
Asunto(s)
Apoptosis/efectos de los fármacos , Butanos/química , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Lignanos/toxicidad , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HL-60 , Células HeLa , Humanos , Lignanos/síntesis química , Lignanos/química , Conformación Molecular , Relación Estructura-ActividadRESUMEN
All the stereoisomers of butanol type 1,7-seco-2,7'-cyclolignane were stereoselectively synthesized by employing (S)- and (R)-Evans' auxiliaries to construct the stereochemistry. (+)- and (-)-Kadangustin J and their diastereomers were also prepared. The optical purity of the synthesized butanol type 1,7-seco-2,7'-cyclolignane was more than 99%ee.