Synthesis and cytotoxic activity of α-santonin derivatives

Ten alpha-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10 alpha-acetoxy-3-oxo-1,7 alpha H,6,11 beta H-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10 alpha-hydroxy-3-oxo-1,7aH,6,11 beta H-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using a-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of a-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7 alpha H,6 beta H,11(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7 alpha H,6 beta H-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10 alpha-acetoxy-3-oxo-1,7 alpha H,6 beta H-guai-4, 11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10 alpha-acetoxy-3 beta-hydroxy-1,7 alpha H,6,11 beta H-guai-4-en-6,12-olide (10) and 3 beta,10 alpha-hydroxy-1,7 alpha H,6,11 beta H-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC50 values in the range of 0.36-14.5 mu M, showed as common structural feature the presence of an alpha-methylidene-gamma-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development. (C) 2009 Elsevier Masson SAS. All rights reserved.