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A Green Light-Triggerable RGD Peptide for Photocontrolled Targeted Drug Delivery: Synthesis and Photolysis Studies
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2016-11-16 00:00:00 , DOI: 10.1021/acs.joc.6b02415 Albert Gandioso 1 , Marc Cano 1 , Anna Massaguer 2 , Vicente Marchán 1
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2016-11-16 00:00:00 , DOI: 10.1021/acs.joc.6b02415 Albert Gandioso 1 , Marc Cano 1 , Anna Massaguer 2 , Vicente Marchán 1
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We describe for the first time the synthesis and photochemical properties of a coumarin-caged cyclic RGD peptide and demonstrate that uncaging can be efficiently performed with biologically compatible green light. This was accomplished by using a new dicyanocoumarin derivative (DEAdcCE) for the protection of the carboxyl function at the side chain of the aspartic acid residue, which was selected on the basis of Fmoc-tBu SPPS compatibility and photolysis efficiency. The shielding effect of a methyl group incorporated in the coumarin derivative near the ester bond linking both moieties in combination with the use of acidic additives such as HOBt or Oxyma during the basic Fmoc-removal treatment were found to be very effective for minimizing aspartimide-related side reactions. In addition, a conjugate between the dicyanocoumarin-caged cyclic RGD peptide and ruthenocene, which was selected as a metallodrug model cargo, has been synthesized and characterized. The fact that green-light triggered photoactivation can be efficiently performed both with the caged peptide and with its ruthenocenoyl bioconjugate reveals great potential for DEAdcCE-caged peptide sequences as selective drug carriers in the context of photocontrolled targeted anticancer strategies.
中文翻译：
用于光控靶向药物传递的绿色可触发RGD肽：合成和光解研究
我们首次描述了香豆素笼型环状RGD肽的合成和光化学性质，并证明可以通过生物相容的绿光有效地进行解笼。这是通过使用新的双氰基香豆素衍生物（DEAdcCE）来保护天冬氨酸残基侧链上的羧基功能而实现的，该功能是根据Fmoc-tBu SPPS的相容性和光解效率选择的。发现在碱性Fmoc去除处理中结合香豆素衍生物中连接两个部分的酯键附近的甲基的屏蔽作用与在酸性Fmoc去除处理中使用酸性添加剂（如HOBt或Oxyma）相结合，对于减少与天冬酰胺相关的物质非常有效副反应。此外，合成并表征了被选为金属药物模型货物的双氰基香豆素笼蔽的环状RGD肽和钌茂金属之间的缀合物。可以用笼状肽及其ruthenocenoyl生物共轭物有效地执行绿光触发的光激活这一事实，揭示了在光控靶向抗癌策略的背景下，DEAdcCE笼状肽序列作为选择性药物载体的巨大潜力。
更新日期：2016-11-16
中文翻译：
用于光控靶向药物传递的绿色可触发RGD肽：合成和光解研究
我们首次描述了香豆素笼型环状RGD肽的合成和光化学性质，并证明可以通过生物相容的绿光有效地进行解笼。这是通过使用新的双氰基香豆素衍生物（DEAdcCE）来保护天冬氨酸残基侧链上的羧基功能而实现的，该功能是根据Fmoc-tBu SPPS的相容性和光解效率选择的。发现在碱性Fmoc去除处理中结合香豆素衍生物中连接两个部分的酯键附近的甲基的屏蔽作用与在酸性Fmoc去除处理中使用酸性添加剂（如HOBt或Oxyma）相结合，对于减少与天冬酰胺相关的物质非常有效副反应。此外，合成并表征了被选为金属药物模型货物的双氰基香豆素笼蔽的环状RGD肽和钌茂金属之间的缀合物。可以用笼状肽及其ruthenocenoyl生物共轭物有效地执行绿光触发的光激活这一事实，揭示了在光控靶向抗癌策略的背景下，DEAdcCE笼状肽序列作为选择性药物载体的巨大潜力。
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