Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, United States.
J Nat Prod. 2012 Mar 23;75(3):385-93. doi: 10.1021/np200797x. Epub 2012 Feb 10.
Toward the objective of designing a structurally modified analogue of the combretastatin A-4 phosphate prodrug (1b) with the potential for increased specificity toward thyroid carcinoma, synthesis of a series of iodocombstatin phosphate (11a-h) and diiodocombstatin phosphate prodrugs (12a-h) has been accomplished. The diiodo series was obtained via 8a and 9c from condensation of 4 and 6, and the iodo sequence involved a parallel pathway. Both series of iodocombstatins were found to display significant to powerful inhibition of the growth of a panel of human cancer cell lines and of the murine P388 lymphocytic leukemia cell line. Of the diiodo series, 12a was also found to markedly inhibit growth of pediatric neuroblastoma, and monoiodocombstatin 9a strongly inhibited HUVEC growth. Overall, the strongest activity was found against the breast, CNS, leukemia, lung, and prostate cancer cell lines and the least activity against the pancreas and colon lines. Parallel biological investigations of tubulin interaction, antiangiogenesis, and antimicrobial effects were also conducted.
为了设计具有增加甲状腺癌特异性潜力的 combretastatin A-4 磷酸盐前药（1b）的结构修饰类似物这一目标，已经完成了一系列碘代 combstatin 磷酸盐（11a-h）和二碘代 combstatin 磷酸盐前药（12a-h）的合成。二碘系列是通过 8a 和 9c 从 4 和 6 的缩合获得的，碘代序列涉及平行途径。这两个碘代 combstatin 系列都被发现对一系列人类癌细胞系和鼠 P388 淋巴细胞白血病细胞系的生长具有显著到强大的抑制作用。在二碘系列中，12a 还被发现明显抑制小儿神经母细胞瘤的生长，而单碘代 combstatin 9a 强烈抑制 HUVEC 的生长。总的来说，对乳腺癌、中枢神经系统癌、白血病、肺癌和前列腺癌细胞系的活性最强，对胰腺和结肠细胞系的活性最弱。还进行了平行的微管相互作用、抗血管生成和抗菌作用的生物学研究。
