Glycohub, Inc. , 4070 Truxel Road, Sacramento, California 95834, United States.
Department of Chemistry, University of California , One Shields Avenue, Davis, California 95616, United States.
J Org Chem. 2017 Dec 15;82(24):13152-13160. doi: 10.1021/acs.joc.7b02167. Epub 2017 Nov 22.
Necrotizing enterocolitis (NEC) is one of the most common and devastating intestinal disorders in preterm infants. Therapies to meet the clinical needs for this special and highly vulnerable population are extremely limited. A specific human milk oligosaccharide (HMO), disialyllacto-N-tetraose (DSLNT), was shown to contribute to the beneficial effects of breastfeeding as it prevented NEC in a neonatal rat model and was associated with lower NEC risk in a human clinical cohort study. Herein, gram-scale synthesis of two DSLNT analogs previously shown to have NEC preventing effect is described. In addition, four novel disialyl glycans have been designed and synthesized by enzymatic or chemoenzymatic methods. Noticeably, two disialyl tetraoses have been produced by enzymatic sialylation of chemically synthesized thioethyl β-disaccharides followed by removal of the thioethyl aglycon. Dose-dependent and single-dose comparison studies showed varying NEC-preventing effects of the disialyl glycans in neonatal rats. This study helps to refine the structure requirement of the NEC-preventing effect of disialyl glycans and provides important dose-dependent information for using DSLNT analogs as potential therapeutics for NEC prevention in preterm infants.
坏死性小肠结肠炎（NEC）是早产儿最常见和最具破坏性的肠道疾病之一。针对这一特殊且极其脆弱人群的治疗方法极为有限。一种特定的人乳寡糖（HMO），二岩藻糖基乳糖-N-四糖（DSLNT），已被证明可通过预防新生大鼠模型中的 NEC 来发挥母乳喂养的有益作用，并且与人类临床队列研究中的较低 NEC 风险相关。本文描述了先前显示具有预防 NEC 作用的两种 DSLNT 类似物的克级合成。此外，还通过酶法或化学-酶法设计和合成了四种新型二岩藻糖。值得注意的是，通过化学合成的硫代乙基β-二糖的酶促唾液酸化，然后去除硫代乙基糖苷，产生了两种二岩藻四糖。剂量依赖性和单次剂量比较研究表明，新生大鼠中二岩藻聚糖的 NEC 预防作用存在差异。这项研究有助于细化二岩藻糖预防 NEC 作用的结构要求，并为使用 DSLNT 类似物作为预防早产儿 NEC 的潜在治疗方法提供重要的剂量依赖性信息。
