Alkyl vs. aryl modifications: a comparative study on modular modifications of triphenylphosphonium mitochondrial vectors,RSC Chemical Biology

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Alkyl vs. aryl modifications: a comparative study on modular modifications of triphenylphosphonium mitochondrial vectors
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2021-08-25 , DOI: 10.1039/d1cb00099c
How Chee Ong ₁ , João T S Coimbra ₂ , Germain Kwek ₁ , Maria J Ramos ₂ , Bengang Xing ₁ , Pedro A Fernandes ₂ , Felipe García ₁

Affiliation

Triphenylphosphonium (TPP⁺) moieties are commonly conjugated to drug molecules to confer mitochondrial selectivity due to their positive charge and high lipophilicity. Although optimisation of lipophilicity can be achieved by modifying the length of the alkyl linkers between the TPP⁺ moiety and the drug molecule, it is not always possible. While methylation of the TPP⁺ moiety is a viable alternative to increase lipophilicity and mitochondrial accumulation, there are no studies comparing these two separate modular approaches. Thus, we have systematically designed, synthesised and tested a range of TPP⁺ molecules with varying alkyl chain lengths and degree of aryl methylation to compare the two modular methodologies for modulating lipophilicity. The ability of aryl/alkyl modified TPP⁺ to deliver cargo to the mitochondria was also evaluated by confocal imaging with a TPP⁺-conjugated fluorescein-based fluorophore. Furthermore, we have employed molecular dynamics simulations to understand the translocation of these molecules through biological membrane model systems. These results provide further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications.

中文翻译：

烷基与芳基修饰：三苯基鏻线粒体载体模块化修饰的比较研究

三苯基鏻 (TPP ⁺ ) 部分通常与药物分子缀合，以赋予线粒体选择性，因为它们具有正电荷和高亲脂性。尽管可以通过修改 TPP ⁺部分和药物分子之间的烷基接头的长度来优化亲脂性，但这并不总是可行的。虽然 TPP ⁺部分的甲基化是增加亲脂性和线粒体积累的可行替代方案，但没有研究比较这两种单独的模块化方法。因此，我们系统地设计、合成和测试了一系列 TPP ⁺具有不同烷基链长度和芳基甲基化程度的分子，以比较调节亲脂性的两种模块化方法。芳基/烷基修饰的 TPP ⁺将货物输送到线粒体的能力也通过使用 TPP ^{+ -}缀合的荧光素基荧光团的共聚焦成像进行评估。此外，我们采用分子动力学模拟来了解这些分子通过生物膜模型系统的易位。这些结果提供了对该过程的热力学以及烷基和芳基模块化修饰的影响的进一步见解。

更新日期：2021-09-07

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