Kithsiri Wijeratne E M, Liu Manping X, Kantipudi Narendra B, Brochini Claudia B, Leslie Gunatilaka A A, Canfield Louise M
Southwest Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, College of Agriculture and Life Sciences, The University of Arizona, Tucson, AZ 85706-6800, USA.
Bioorg Med Chem. 2006 Dec 1;14(23):7875-9. doi: 10.1016/j.bmc.2006.07.057.
Synthesis of the beta-carotene oxidation product, 2,3-dihydro-5,8-endoperoxy-beta-apo-carotene-13-one (1) was achieved in six steps starting from beta-ionone. Photo-oxygenation of all trans-retinoic acid (8) and 13-cis-retinoic acid (9) produced a mixture of 5S*,8S*-epidioxy-5,8-dihydroretinoic acid (10) and 13-cis-5S*,8S*-epidioxy-5,8-dihydroretinoic acid (11). Methylation of the crude photo-oxygenation mixture afforded the corresponding methyl esters 12 and 13, respectively, both of which underwent ready aerial oxidation yielding hitherto unknown oxidation products of retinoic acid identified as methyl 5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (14) and methyl 13-cis-5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (15). Evaluation of 1, all trans-retinoic acid (8), 13-cis-retinoic acid (9), and the photo-oxygenation products 10-15 in a panel of five cancer cell lines showed 1 to be inactive and that 11 is significantly cytotoxic compared with the other retinoic acid analogs suggesting the requirement of the carboxylic acid moiety and the cis-geometry of the 13(14) double bond for cytotoxic activity.
从β-紫罗兰酮开始，经过六步反应实现了β-胡萝卜素氧化产物2,3-二氢-5,8-内过氧-β-阿朴胡萝卜素-13-酮（1）的合成。全反式视黄酸（8）和13-顺式视黄酸（9）的光氧化反应生成了5S*,8S*-环氧-5,8-二氢视黄酸（10）和13-顺式-5S*,8S*-环氧-5,8-二氢视黄酸（11）的混合物。粗光氧化混合物的甲基化反应分别得到了相应的甲酯12和13，二者均易于发生空气氧化，生成了迄今未知的视黄酸氧化产物，鉴定为5S*,8S*-环氧-9,10β-环氧-5,8,9,10-四氢视黄酸甲酯（14）和13-顺式-5S*,8S*-环氧-9,10β-环氧-5,8,9,10-四氢视黄酸甲酯（15）。在一组五种癌细胞系中对1、全反式视黄酸（8）、13-顺式视黄酸（9）以及光氧化产物10 - 15进行评估，结果显示1无活性，并且与其他视黄酸类似物相比，11具有显著的细胞毒性，这表明细胞毒性活性需要羧酸部分以及13(14)双键的顺式构型。
