Arantes Francisco F P, Barbosa Luiz C A, Alvarenga Elson S, Demuner Antônio J, Bezerra Daniel P, Ferreira José R O, Costa-Lotufo Letícia V, Pessoa Cláudia, Moraes Manoel O
Department of Chemistry, Federal University of Viçosa, Av. P.H. Rolfs, S/N, CEP 36570-000 Viçosa, MG, Brazil.
Eur J Med Chem. 2009 Sep;44(9):3739-45. doi: 10.1016/j.ejmech.2009.03.036. Epub 2009 Apr 5.
Ten alpha-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10alpha-acetoxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10alpha-hydroxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using alpha-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 alpha-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7alphaH,6betaH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7alphaH,6betaH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10alpha-acetoxy-3-oxo-1,7alphaH,6betaH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10alpha-acetoxy-3beta-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (10) and 3beta,10alpha-hydroxy-1,7alphaH,6,11betaH-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 IC(50) values in the range of 0.36-14.5 microM, 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.
合成了10种山道年α-衍生物，产率适中至较高。以山道年α（1）为起始原料，通过不同的光化学反应制备了4种衍生物，即10α-乙酰氧基-3-氧代-1,7αH,6,11βH-愈创木-4-烯-6,12-内酯（2）、异佛手柑内酯酸（3）、10α-羟基-3-氧代-1,7αH,6,11βH-愈创木-4-烯-6,12-内酯（4）和脱氢山道年（5）。这些转化反应在无水乙酸、乙酸/水（1:1 v/v）或乙腈中进行，使用不同类型的反应器和紫外光源。用二异丙基氨基锂（LDA）处理山道年α（1），然后用苯基硒氯捕获有机锂，得到化合物3-氧代-7αH,6βH,11-（苯基硒基）-桉叶-1,4-二烯-6,12-内酯（6）。随后用过氧化氢处理化合物6，得到3-氧代-7αH,6βH-桉叶-1,4,11-三烯-6,12-内酯（7）。化合物7的光化学反应导致形成11,13-脱氢脱氢山道年（8）和10α-乙酰氧基-3-氧代-1,7αH,6βH-愈创木-4,11-二烯-6,12-内酯（9）。用硼氢化钠还原化合物2和4，得到衍生物10α-乙酰氧基-3β-羟基-1,7αH,6,11βH-愈创木-4-烯-6,12-内酯（10）和3β,10α-二羟基-1,7αH,6,11βH-愈创木-4-烯-6,12-内酯（11）。评估了合成化合物对癌细胞系HL-60（白血病）、SF-295（中枢神经系统）、HCT-8（结肠）、MDA-MB-435（黑色素瘤）、UACC-257（黑色素瘤）、A549（肺癌）、OVACAR-8（卵巢癌）、A704（肾癌）和PC3（前列腺癌）的细胞毒性。活性较高的化合物，其半数抑制浓度（IC50）值在0.36 - 14.5微摩尔范围内，其结构中共同的特征是存在α-亚甲基-γ-丁内酯部分。对正常细胞（外周血单核细胞）进行的生物学试验表明，这些化合物对癌细胞系具有选择性。修饰后的内酯似乎是抗癌药物开发中有趣的先导结构。
