Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Sapporo 060-8589, Japan.
Bioorg Med Chem Lett. 2013 Sep 15;23(18):5140-4. doi: 10.1016/j.bmcl.2013.07.016. Epub 2013 Jul 19.
Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5-triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type I and II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10 μM. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC.
合成了麦考酚酸（MPA）在 C-6'位的十个衍生物，并对这些衍生物、MPA 和麦考酚羟肟酸（MPHA）进行了结构-活性关系研究，发现了 N-(2,3,5-三唑基)麦考酚酰胺 4、（7'S）麦考酚环氧酮 9 和（7'R）麦考酚环氧酮 10，它们对人肌苷-5'-单磷酸脱氢酶（IMPDH）I 型和 II 型具有很强的抑制活性，对人白血病 K562 细胞也具有抗增殖活性。化合物 4、9 和 10 在 K562 细胞中具有诱导红细胞分化的活性。在 K562 细胞中，补充鸟苷可减弱化合物 4 和 10 对 IMPDH 的抑制作用。相比之下，9 的情况则不明显。化合物 9 在 10 μM 时可轻微抑制 K562 细胞核裂解物中 HDAC 的酶活性。这些观察结果表明，4、9 和 10 的主要靶标是 IMPDH，而化合物 9 部分抑制了某种类型的 HDAC。
