Abstract:
Amide bonds are one of the most prevalent phenomena in nature and are utilized frequently in drug and material design. However, forming amide bonds is not always efficient or high yielding, particularly when the amine used to conjugate to a carboxylic acid is a weak nucleophile. This limitation precludes many useful amino compounds from participating in conjugation reactions to form amides. A particularly valuable amino compound, which is also a very weak nucleophile, is the amino porphyrin, valued for its role as a photosensitizer, fluorescent agent, catalyst, or, upon metalation, even a very efficient contrast agent for magnetic resonance imaging (MRI). In this work, we propose fast and high-yield coupling of an unreactive amine - the amino porphyrin - to carboxylic acid via isothiocyanate conjugation. Reactions can be achieved in one step at room temperature in one hour, achieving quantitative conversion and near perfect selectivity. Both metalated and unmetalated porphyrin, as well as fluorescein isothiocyanate (FITC), demonstrated efficient conjugation. To illustrate the value of the proposed method, we created a new blood-pool MRI contrast agent that reversibly binds to serum albumin. This new blood-pool agent, known as MITC-Deox (MRI isothiocyanate that links with deoxycholic acid), substantially reduced T1 relaxation times in blood vessels in mice, remained stable for 1 hour, cleared from blood by 24 hours, and was eliminated from the body after 4 days. The proposed method for efficient amide formation is a superior alternative to existing coupling methods, opening a door to novel synthesis of MRI contrast agents and beyond.
摘要:
酰胺键是自然界中最普遍的现象之一,经常用于药物和材料设计。然而,形成酰胺键并不总是高效或高产的,特别是当用于与羧酸缀合的胺是弱亲核试剂时。这种限制排除了许多有用的氨基化合物参与缀合反应以形成酰胺。一种特别有价值的氨基化合物,它也是一种非常弱的亲核试剂,是氨基卟啉,因为它作为光敏剂的作用而受到重视,荧光剂,催化剂,或者,在金属化时,甚至是用于磁共振成像(MRI)的非常有效的造影剂。在这项工作中,我们提出了通过异硫氰酸酯共轭将非反应性胺-氨基卟啉-与羧酸快速高产率偶联。反应可以在室温下在一小时内一步完成,实现定量转化和接近完美的选择性。金属化和未金属化卟啉,以及异硫氰酸荧光素(FITC),证明了有效的缀合。为了说明所提出方法的价值,我们创造了一种新的与血清白蛋白可逆结合的血池MRI造影剂.这个新的血池特工,称为MITC-Deox(与脱氧胆酸连接的MRI异硫氰酸酯),大大减少了小鼠血管中的T1弛豫时间,保持稳定1小时,24小时后从血液中清除,并在4天后从体内清除。所提出的高效酰胺形成方法是现有偶联方法的优越替代方法,为MRI造影剂的新型合成和超越打开了一扇门。