Coyne Cody P, Narayanan Lakshmi
Department of Basic Sciences, College of Veterinary Medicine, Wise Center, Mississippi State University, Mississippi State, MS, USA.
College of Veterinary Medicine, Wise Center, Mississippi State University, Mississippi State, MS, USA.
Chem Biol Drug Des. 2017 Mar;89(3):379-399. doi: 10.1111/cbdd.12845. Epub 2016 Dec 20.
One molecular-based approach that increases potency and reduces dose-limited sequela is the implementation of selective 'targeted' delivery strategies for conventional small molecular weight chemotherapeutic agents. Descriptions of the molecular design and organic chemistry reactions that are applicable for synthesis of covalent gemcitabine-monophosphate immunochemotherapeutics have to date not been reported. The covalent immunopharmaceutical, gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R] was synthesized by reacting gemcitabine with a carbodiimide reagent to form a gemcitabine carbodiimide phosphate ester intermediate which was subsequently reacted with imidazole to create amine-reactive gemcitabine-(5'-phosphorylimidazolide) intermediate. Monoclonal anti-IGF-1R immunoglobulin was combined with gemcitabine-(5'-phosphorylimidazolide) resulting in the synthetic formation of gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R]. The gemcitabine molar incorporation index for gemcitabine-(5'-phosphoramidate)-[anti-IGF-R1] was 2.67:1. Cytotoxicity Analysis - dramatic increases in antineoplastic cytotoxicity were observed at and between the gemcitabine-equivalent concentrations of 10 M and 10 M where lethal cancer cell death increased from 0.0% to a 93.1% maximum (100.% to 6.93% residual survival), respectively. Advantages of the organic chemistry reactions in the multistage synthesis scheme for gemcitabine-(5'-phosphoramidate)-[anti-IGF-1R] include their capacity to achieve high chemotherapeutic molar incorporation ratios; option of producing an amine-reactive chemotherapeutic intermediate that can be preserved for future synthesis applications; and non-dedicated organic chemistry reaction scheme that allows substitutions of either or both therapeutic moieties, and molecular delivery platforms.
一种提高效力并减少剂量限制后遗症的基于分子的方法是对传统小分子化疗药物实施选择性“靶向”递送策略。迄今为止，尚未有关于适用于合成共价吉西他滨-单磷酸免疫化疗药物的分子设计和有机化学反应的描述。共价免疫药物吉西他滨-(5'-磷酰胺)-[抗IGF-1R] 的合成方法是，使吉西他滨与碳二亚胺试剂反应形成吉西他滨碳二亚胺磷酸酯中间体，该中间体随后与咪唑反应生成胺反应性吉西他滨-(5'-磷酰咪唑)中间体。单克隆抗IGF-1R免疫球蛋白与吉西他滨-(5'-磷酰咪唑)结合，从而合成形成吉西他滨-(5'-磷酰胺)-[抗IGF-1R]。吉西他滨-(5'-磷酰胺)-[抗IGF-R1] 的吉西他滨摩尔掺入指数为2.67:1。细胞毒性分析——在吉西他滨等效浓度为10 μM和10 μM时以及两者之间观察到抗肿瘤细胞毒性显著增加，其中致死癌细胞死亡率分别从0.0% 增至最大值93.1%（残余存活率从100.% 降至6.93%）。吉西他滨-(5'-磷酰胺)-[抗IGF-1R] 多步合成方案中有机化学反应的优点包括能够实现高化疗摩尔掺入率；可选择生产一种可保存以备未来合成应用的胺反应性化疗中间体；以及非专用有机化学反应方案，该方案允许替换一个或两个治疗部分以及分子递送平台。
