Abstract
The aim of this study was to investigate the in vitro cellular activity of novel spiroisoxazoline type compounds against normal and cancer cell lines from lung tissue (Hs888Lu), neuron-phenotypic cells (SH-SY5Y), neuroblastoma (SH-SY5Y), human histiocytic lymphoma (U937), lung cancer (A549), and leukaemia (HL-60). Our bioassay program revealed that the spiroisoxazoline type compounds show cytotoxicity only in lymphoma cell lines, which is in contrast with the pyrrolidine precursor of these spiroisoxazoline compounds, where significant cytotoxicity is seen in all normal and cancer cell lines. These data suggest a tumour-specific mechanism of action. In addition these data also show that spiroisoxazoline compounds are non-toxic in the human neuron-phenotypic neuroblastoma SH-SY5Y cell line, and furthermore that they might protect cells from neurodegenerative disease.
Highlights
In a continuous effort towards the synthesis of bioactive pyrrolidine type compounds [1,2,3,4], our group was able to synthesize some novel spiroisoxazoline compounds sharing a pyrrolidine and isoxazoline rings in their skeleton, and produce a variety of synthetic structures
A survey of the literature revealed that no studies on the potential anticancer and neuroprotection activity of pyrrolidine and spiroisoxazoline type compounds had been reported, various bioactivities have been reported previously [7, 13,14,15,16,17]
Our results demonstrate that YA2 and YA3 can elicit significant cytotoxic effects by induction of apoptosis on lymphoma U937 cells
Summary
In a continuous effort towards the synthesis of bioactive pyrrolidine type compounds [1,2,3,4], our group was able to synthesize some novel spiroisoxazoline compounds sharing a pyrrolidine and isoxazoline rings in their skeleton, and produce a variety of synthetic structures. Natural extracts and synthetic pyrrolidine and spiroisoxazoline compounds are gaining more and more importance because of their remarkable biological properties. These recent observations have stimulated our interest in screening of the potential anticancer and neuroprotective activities of three novel compounds (see Figure 1), namely 1-benzyl-3,3-dimethyl-5-methylenepyrrolidin-2,4-dione (in this study coded as YA1), (5S)-6-benzyl-8,8-dimethyl-1-oxa-3-phenyl-2,6-diazaspiro{4.4}non-2-ene7,9-dione (coded as YA2) [3] and (5R)-ethyl 6-benzyl-8,8-dimethyl-7,9-dioxo-1-oxa-2,6diazaspiro{4.4}non-2-ene-3-carboxylate (coded as YA3) against a panel of normal and cancer cell lines. The evidence shows that the pyrrolidines exert a number of biological effects and that there is unlikely to be no single predominant mode of action that is common to all pyrrolidine compounds [7]
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