Synthetic analogues of TNP-470 and ovalicin reveal a common molecular basis for inhibition of angiogenesis and immunosuppression.
Synthetic analogues of TNP-470 and ovalicin reveal a common molecular basis for inhibition of angiogenesis and immunosuppression.
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TNP-470 和卵磷脂的合成类似物揭示了抑制血管生成和免疫抑制的共同分子基础。
DOI：
10.1016/s0968-0896(98)00078-9
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发表时间：
1998
影响因子：
3.5
通讯作者：
J. O. Liu
中科院分区：
文献类型：
--
作者：
B. Turk;Z. Su;J. O. Liu
TNP-470 (1) 是天然产物夫马洁林 (2) 的合成衍生物，可有效抑制体内血管生成和体外内皮细胞培养物的生长。结构相关的天然产物卵磷脂 (3) 也能抑制血管生成，但具有有效的免疫抑制活性。最近发现所有三种药物都结合并抑制相同的靶标——甲硫氨酸氨基肽酶 2 (MetAP2)，这引发了这样的问题：TNP-470 是否也具有免疫抑制作用，以及对 MetAP2 的抑制是否是卵磷脂的两种活性的基础。为了解决这些问题，我们合成了一系列 TNP-470 和卵黄素类似物，并测试了它们抑制内皮细胞或混合淋巴细胞培养物增殖的能力。 TNP-470 及其类似物被发现具有免疫抑制和抗血管生成活性。观察到化合物抑制牛和人内皮细胞生长的能力与抑制小鼠混合淋巴细胞反应（MLR）的能力之间存在很强的相关性，这意味着这两种活性具有共同的分子基础，即抑制 MetAP2。有趣的是，卵黄素和其他几种化合物在人 MLR 中的表现与在小鼠 MLR 或人内皮细胞增殖测定中的表现不同，这表明这些化合物的代谢或摄取可能存在物种特异性和细胞类型特异性差异。
TNP-470 (1), a synthetic derivative of the natural product fumagillin (2), potently inhibits angiogenesis in vivo and the growth of endothelial cell cultures in vitro. The structurally related natural product ovalicin (3) also inhibits angiogenesis but possesses potent immunosuppressive activity. The recent finding that all three drugs bind and inhibit the same target, methionine aminopeptidase 2 (MetAP2), raised the question of whether TNP-470 is also immunosuppressive and whether inhibition of MetAP2 underlies both activities of ovalicin. To address these questions, we synthesized a series of analogues of TNP-470 and ovalicin and tested them for their abilities to inhibit the proliferation of either endothelial cell or mixed lymphocyte cultures. TNP-470 and its analogues were found to possess both immunosuppressive and anti-angiogenic activities. A strong correlation was observed between the ability of compounds to inhibit bovine and human endothelial cell growth and their ability to inhibit the mouse mixed lymphocyte reaction (MLR), implying that the two activities share a common molecular basis, i.e., inhibition of MetAP2. Interestingly, ovalicin and several other compounds behaved differently in the human MLR than in either the mouse MLR or human endothelial cell proliferation assays, pointing to possible species-specific and cell type-specific differences in the metabolism or uptake of these compounds.