Rewcastle G W, Atwell G J, Baguley B C, Boyd M, Thomsen L L, Zhuang L, Denny W A
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
J Med Chem. 1991 Sep;34(9):2864-70. doi: 10.1021/jm00113a027.
A series of 16 analogues of the solid tumor active compound 9-oxo-9H-xanthene-4-acetic acid (XAA), with variations in the acetic acid side chain, have been prepared and evaluated for their ability to cause early haemorrhagic necrosis of colon 38 tumors in mice. The results extend the previous SAR for this class and confirm the necessity for a carboxylic acid group in a fixed disposition with respect to the xanthenone chromophore. None of the compounds showed superior potency to XAA itself, with virtually all alterations in the nature of the anionic center or its geometry with respect to the chromophore greatly reducing or abolishing activity. However, alpha-methylation of the side chain was permissible, and the two enantiomers of 5-methyl-alpha-methyl-XAA were separated and tested. Both were active, but the S-(+) enantiomer was much more dose-potent than the R-(-) enantiomer, in both the in vivo tumor necrosis assay and an in vitro assay measuring the stimulation of nitric oxide production by macrophages. This suggests that the enantiomers have different intrinsic activities, rather than differing in their vivo metabolism.
已制备了一系列16种实体瘤活性化合物9-氧代-9H-呫吨-4-乙酸（XAA）的类似物，其乙酸侧链有所变化，并评估了它们在小鼠体内引起结肠38肿瘤早期出血性坏死的能力。结果扩展了此类化合物先前的构效关系（SAR），并证实了相对于呫吨酮发色团，在固定位置存在羧酸基团的必要性。没有一种化合物表现出比XAA本身更强的效力，实际上阴离子中心的性质或其相对于发色团的几何结构的所有改变都会大大降低或消除活性。然而，侧链的α-甲基化是可行的，5-甲基-α-甲基-XAA的两种对映体被分离并进行了测试。在体内肿瘤坏死试验和测量巨噬细胞一氧化氮产生刺激的体外试验中，两者均有活性，但S-(+)对映体的剂量效力比R-(-)对映体高得多。这表明对映体具有不同的内在活性，而不是在体内代谢方面存在差异。
