Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
J Org Chem. 2022 Sep 2;87(17):11593-11601. doi: 10.1021/acs.joc.2c01229. Epub 2022 Aug 11.
A modular synthetic process enables two or four shielding arms to be appended strategically over the fluorochromes of near-infrared cyanine heptamethine dyes to create hydrophilic analogs of clinically approved indocyanine green. A key synthetic step is the facile substitution of a heptamethine 4'-Cl atom by a phenol bearing two triethylene glycol chains. The lead compound is a heptamethine dye with four shielding arms, and a series of comparative spectroscopy studies showed that the shielding arms (a) increased dye photostability and chemical stability and (b) inhibited dye self-aggregation and association with albumin protein. In mice, the dye cleared from the blood primarily through the renal pathway rather than the biliary pathway for . This change in biodistribution reflects the much smaller hydrodynamic diameter of the shielded hydrophilic analog compared to the 67 kDa size of the /albumin complex. An attractive feature of versatile synthetic chemistry is the capability to systematically alter the dye's hydrodynamic diameter. The sterically shielded hydrophilic dye platform is well-suited for immediate incorporation into dynamic contrast-enhanced (DCE) spectroscopy or imaging protocols using the same cameras and detectors that have been optimized for .
一种模块化的合成工艺可以在近红外花菁七甲川染料的荧光团上策略性地附加两个或四个屏蔽臂，从而创建临床批准的吲哚菁绿的亲水类似物。一个关键的合成步骤是通过具有两个三乙二醇链的苯酚轻松取代七甲川 4'-Cl 原子。该先导化合物是一种具有四个屏蔽臂的七甲川染料，一系列比较光谱研究表明，屏蔽臂(a)提高了染料的光稳定性和化学稳定性，(b)抑制了染料的自聚集和与白蛋白蛋白的结合。在小鼠中，该染料主要通过肾脏途径而不是胆汁途径从血液中清除，这反映了与 /白蛋白复合物的 67 kDa 大小相比，屏蔽的亲水性类似物的水动力直径小得多。多功能合成化学的一个吸引人的特点是能够系统地改变染料的水动力直径。这种受空间位阻保护的亲水性染料平台非常适合立即纳入动态对比增强（DCE）光谱学或成像方案，使用已经针对 优化的相同相机和探测器。
