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Development of Clickable Monophosphoryl Lipid A Derivatives toward Semisynthetic Conjugates with Tumor-Associated Carbohydrate Antigens
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2017-11-14 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01234
Marcello Ziaco 1 , Sabina Górska 2 , Serena Traboni 1 , Agnieszka Razim 2 , Angela Casillo 1 , Alfonso Iadonisi 1 , Andrzej Gamian 2 , Maria Michela Corsaro 1 , Emiliano Bedini 1
Affiliation  

A semisynthetic strategy to obtain monophosphoryl lipid A derivatives equipped with clickable (azide, alkyne, double bond, or thiol precursor) moieties, starting from the native lipid A isolated from Escherichia coli, is presented. These lipid A derivatives can be conjugated with other interesting biomolecules, such as tumor-associated carbohydrate antigens (TACAs). In this way, the immunostimulant activity of monophosphoryl lipid A can significantly improve the immunogenicity of TACAs, thus opening access to potential self-adjuvant anticancer vaccine candidates. A monophosphoryl lipid A–Thomson-Friedenreich (TF) antigen conjugate was obtained to demonstrate the feasibility of this methodology, which stands as a valuable, rapid, and scalable alternative to the highly complex approaches of total synthesis recently reported to the same aim. A preliminary evaluation of the immunological activity of this conjugate as well as of other semisynthetic lipid A derivatives was also reported.

中文翻译:

可点击的单磷酰脂质A衍生物与肿瘤相关的碳水化合物抗原的半合成缀合物的发展。

从从大肠杆菌中分离的天然脂质A开始,获得具有可点击部分(叠氮基,炔烃,双键或硫醇前体)的单磷酰脂质A衍生物的半合成策略, 被表达。这些脂质A衍生物可以与其他有趣的生物分子,例如肿瘤相关的碳水化合物抗原(TACA)缀合。以这种方式,单磷酰基脂质A的免疫刺激活性可以显着改善TACA的免疫原性,从而为潜在的自佐剂抗癌疫苗候选者打开了大门。获得了单磷酰脂质A–Thomson-Friedenreich(TF)抗原偶联物,以证明该方法的可行性,该方法可作为最近报导于同一目标的高度复杂的全合成方法的一种有价值,快速且可扩展的选择。还报道了对该缀合物以及其他半合成脂质A衍生物的免疫活性的初步评估。
更新日期:2017-11-15
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