Synthesis and anticancer activity of novel spiro-isoxazoline and spiro-isoxazolidine derivatives of -santonin.

Khazir J, Singh PP, Reddy DM, Hyder I, Shafi S, Sawant SD, Chashoo G, Mahajan A, Alam MS, Saxena AK, Arvinda S, Gupta BD, Kumar HM. Source
Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Jammu 180001, India.
Abstract
In the present study, novel spiro derivatives of -santonin were prepared and tested for their anticancer activity against a panel of six human cancer cell lines. Spiro-isoxazoline and spiro-isoxazolidine derivatives have been generated on C-ring of -santonin (-methylene--butyrolactone) by the 1,3-dipolar cycloaddition of -santonin derivative 6 with nitrile oxides 7 and nitrones 9 respectively. Among all, compound 10b had shown IC50 of 0.01, 0.5 and 0.3 M against PC-3, THP-1 and MCF-7 cell lines respectively. Further, flow cytometry studies showed that PC-3 cells treated with the spiro-isoxazolidine derivative 10b were arrested in the sub G1 phase of the cell cycle in a concentration dependent manner. The spiro-isoxazolidine derivative 10b also showed concentration dependent inhibitory activity against NF-B, p65 with 57% inhibition in 24 h at 10 M.

-Santonin derived new series of 1,2,3-triazoles synthesized through Azide-Alkyne Huisgen 1,3-dipolar cycloaddition reaction between substituted aryl azide and a propargylated -desmotrosantonin were bio-evaluated for their diminutive effect on ConA induced T-cell and LPS induced B-cell proliferation. Interestingly, most of the synthesized compounds showed better immunosuppressant activity than -santonin. Triazole derivatives 9, 10, 17, 18, 29, and 30 displayed significant diminutive effect on cell proliferation. Compounds 12 and 13 were found selective against ConA T-cell proliferation exhibiting >90% inhibition at 1 10(-6) M concentration. The present study resulted in identification of several triazole derivatives as effective immunosuppressive agents. - See more at: http://www.sigmaaldrich.com/catalog/papers/23314050#sthash.AlJIYasN.dpuf