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Triple, Mutually Orthogonal Bioorthogonal Pairs through the Design of Electronically Activated Sulfamate-Containing Cycloalkynes
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-10-21 , DOI: 10.1021/jacs.0c06725 Yun Hu 1 , Jessica M Roberts 1 , Henry R Kilgore 2 , Amirah S Mat Lani 1 , Ronald T Raines 2 , Jennifer M Schomaker 1
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-10-21 , DOI: 10.1021/jacs.0c06725 Yun Hu 1 , Jessica M Roberts 1 , Henry R Kilgore 2 , Amirah S Mat Lani 1 , Ronald T Raines 2 , Jennifer M Schomaker 1
Affiliation
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Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds that are capable of fast and predictable reactions. The ability to easily modify S-, N-, and O-containing cyclooctynes (SNO-OCTs) enables electronic tuning of various SNO-OCTs to influence their cycloaddition rates with Type I-III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant reaction rate enhancements of a difluorinated SNO-OCT derivative, as compared to the parent scaffold, were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 5.13 M-1 s-1. Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.
中文翻译：
通过电子激活的含氨基磺酸盐的环炔的设计获得三重、相互正交的生物正交对
对相互排斥的生物正交标记试剂对的兴趣继续推动能够快速且可预测反应的新化合物的设计。能够轻松修饰含 S、N 和 O 的环辛炔 (SNO-OCT)，从而能够对各种 SNO-OCT 进行电子调谐，以影响其与 I-III 型偶极子的环加成速率。与仅基于一种特定偶极子类别的优化相反，可以操纵 SNO-OCT 中炔烃的亲电性来实现不同的反应性并提供相互正交的双连接系统。与母体支架相比，二氟化 SNO-OCT 衍生物的反应速率显着提高，与重氮乙酰胺的环加成反应的二级速率常数超过 5.13 M-1 s-1。采用计算和实验研究来设计包含三个正交反应性的三重连接系统。最后，极性 SNO-OCT 被哺乳动物细胞快速内化，并在细胞质中保持活细胞标记的功能，突出了它们在体外和体内多种应用中的潜力。
更新日期：2020-10-21
中文翻译：
通过电子激活的含氨基磺酸盐的环炔的设计获得三重、相互正交的生物正交对
对相互排斥的生物正交标记试剂对的兴趣继续推动能够快速且可预测反应的新化合物的设计。能够轻松修饰含 S、N 和 O 的环辛炔 (SNO-OCT)，从而能够对各种 SNO-OCT 进行电子调谐，以影响其与 I-III 型偶极子的环加成速率。与仅基于一种特定偶极子类别的优化相反，可以操纵 SNO-OCT 中炔烃的亲电性来实现不同的反应性并提供相互正交的双连接系统。与母体支架相比，二氟化 SNO-OCT 衍生物的反应速率显着提高，与重氮乙酰胺的环加成反应的二级速率常数超过 5.13 M-1 s-1。采用计算和实验研究来设计包含三个正交反应性的三重连接系统。最后，极性 SNO-OCT 被哺乳动物细胞快速内化，并在细胞质中保持活细胞标记的功能，突出了它们在体外和体内多种应用中的潜力。
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