Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo 060-8589, Japan.
Bioorg Med Chem. 2010 Nov 15;18(22):8106-11. doi: 10.1016/j.bmc.2010.09.004. Epub 2010 Sep 18.
Inosine monophosphate dehydrogenases (IMPDHs) are the committed step in de novo guanine nucleotide biosynthesis. There are two separate, but very closely related IMPDH isoenzymes, termed type I and type II. IMPDHs are widely believed to be major targets for cancer and transplantation therapy. Mycophenolic acid (MPA) is a potent inhibitor of IMPDHs. Previously, we found that MPA acted as a latent agonist of this nuclear hormone receptor in U2OS cells, and 6'-hydroxamic acid derivatives of MPA inhibited tubulin-specific histone deacetylase[s] (HDAC[s]) in HeLa cells. Although MPA is a promising lead compound, structure-activity relationships (SARs) for inhibition of IMPDH, and the mechanism action of MPA derivatives have not well been understood. We therefore synthesized, evaluated MPA derivatives as IMPDH inhibitor in vitro and cellular level, and explored their biological function and mechanism in cultured cells. This paper exhibits that (i) functional groups at C-5, C-7, and C-6' positions in MPA are important for inhibitory activity against IMPDH, (ii) it is difficult to improve specificity against IMPDH II by modification of 5-, 7-, and 6'-group, (iii) demethylation of 5-OMe results in increasing hydrophilicity, and lowering cell permeability, (iv) ester bonds of protective groups at C-7 and C-6' positions are hydrolyzed to give MPA in cultures, (v) the effects of a tubulin-specific HDAC[s] inhibitor on proliferation and differentiation are weaker than its inhibitory activity against IMPDH. The present work may provide insight into the development of a new class of drug lead for treating cancer and transplantation.
肌苷单磷酸脱氢酶（IMPDH）是从头合成鸟嘌呤核苷酸的关键步骤。有两种独立但非常密切相关的 IMPDH 同工酶，分别称为 I 型和 II 型。IMPDH 被广泛认为是癌症和移植治疗的主要靶点。霉酚酸（MPA）是 IMPDH 的有效抑制剂。此前，我们发现 MPA 在 U2OS 细胞中作为该核激素受体的潜伏激动剂，MPA 的 6'-羟肟酸衍生物在 HeLa 细胞中抑制微管特异性组蛋白去乙酰化酶[s]（HDAC[s]）。尽管 MPA 是一种很有前途的先导化合物，但 IMPDH 的抑制构效关系（SAR）以及 MPA 衍生物的作用机制尚未得到很好的理解。因此，我们合成并评估了 MPA 衍生物作为 IMPDH 抑制剂在体外和细胞水平上的活性，并在培养细胞中探索了它们的生物学功能和机制。本文表明：（i）MPA 中 C-5、C-7 和 C-6'位的官能团对抑制 IMPDH 活性很重要，（ii）通过修饰 5-、7-和 6'-基团来提高对 IMPDH II 的特异性是困难的，（iii）5-OMe 的去甲基化导致亲水性增加，细胞通透性降低，（iv）C-7 和 C-6'位保护基团的酯键在培养物中水解生成 MPA，（v）微管特异性 HDAC[s]抑制剂对增殖和分化的影响弱于其对 IMPDH 的抑制活性。本工作可能为开发治疗癌症和移植的新型药物先导化合物提供思路。
