Chemistry and biology of dihydroisoxazole derivatives: Selective inhibitors of human transglutaminase 2
Chemistry and biology of dihydroisoxazole derivatives: Selective inhibitors of human transglutaminase 2
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DOI：
10.1016/j.chembiol.2005.02.007
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发表时间：
2005-04-01
影响因子：
--
通讯作者：
Khosla, C
中科院分区：
文献类型：
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作者：
Choi, K;Siegel, M;Khosla, C
3-Halo-4,5-二氢异恶唑是选择性抑制生物系统中亲核活性位点的有吸引力的弹头。制备了一系列 3-溴-4,5-二氢异恶唑化合物，并测试了它们不可逆地抑制人转谷氨酰胺酶 2 (TG2) 的能力，TG2 是一种在多种疾病（包括乳糜泻和某些类型的癌症）的发病机制中发挥重要作用的酶。几种化合物对人 TG2 显示出高度特异性 (k(inh)/K-I > 2000 min(-1)M(-1))，但对生理硫醇（如谷胱甘肽）基本上没有反应性 (k < 1 min(-1)M(-1))。评估了原型二氢异恶唑抑制剂 1b 的药代动力学和药效学特性；在小鼠体内，该化合物表现出良好的口服生物利用度、短的血清半衰期和在小肠组织中有效的 TG2 抑制作用，并且毒性低。它还与 N,N'-双（2-氯乙基）-N-亚硝基脲（BCNU，卡莫司汀）对小鼠难治性胶质母细胞瘤具有良好的协同作用。荧光二氢异恶唑抑制剂 5 促进 HCT-116 细胞胞外表面 TG2 内吞作用的显微镜可视化。总之，这些发现证明了二氢异恶唑化合物作为 TG2 生物学及其在人类疾病中的作用的探针的前景。
3-Halo-4,5-dihydroisoxazoles are attractive warheads for the selective inhibition of nucleophilic active sites in biological systems. A series of 3-bromo-4,5-dihydroisoxazole compounds were prepared and tested for their ability to irreversibly inhibit human transglutaminase 2 (TG2), an enzyme that plays an important role in the pathogenesis of diverse disorders including Celiac Sprue and certain types of cancers. Several compounds showed high specificity for human TG2 (k(inh)/K-I > 2000 min(-1)M(-1)) but essentially no reactivity (k < 1 min(-1)M(-1)) toward physiological thiols such as glutathione. The pharmacokinetic and pharmacodynamic properties of a prototype dihydroisoxazole inhibitor, 1b, were evaluated; in mice the compound showed good oral bioavailability, short serum half-life and efficient TG2 inhibition in small intestinal tissue, and low toxicity. It also showed excellent synergism with N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU, carmustine) against refractory glioblastoma tumors in mice. A fluorescent dihydroisoxazole inhibitor 5 facilitated microscopic visualization of TG2 endocytosis from the extracellular surface of HCT-116 cells. Together, these findings demonstrate the promise of dihydroisoxazole compounds as probes for the biology of TG2 and its role in human disease.