Ong How Chee, Coimbra João T S, Kwek Germain, Ramos Maria J, Xing Bengang, Fernandes Pedro A, García Felipe
School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University 21 Nanyang Link 637371 Singapore
LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto Rua do Campo Alegre s/n 4169-007 Portugal
RSC Chem Biol. 2021 Aug 25;2(6):1643-1650. doi: 10.1039/d1cb00099c. eCollection 2021 Dec 2.
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.
由于其正电荷和高亲脂性，三苯基鏻（TPP）部分通常与药物分子共轭以赋予线粒体选择性。虽然可以通过改变TPP部分与药物分子之间烷基连接子的长度来实现亲脂性的优化，但并非总是可行。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法，但尚无研究比较这两种单独的模块化方法。因此，我们系统地设计、合成并测试了一系列具有不同烷基链长度和芳基甲基化程度的TPP分子，以比较这两种调节亲脂性的模块化方法。还通过使用TPP共轭的基于荧光素的荧光团进行共聚焦成像，评估了芳基/烷基修饰的TPP将货物递送至线粒体的能力。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转运。这些结果为该过程的热力学以及烷基和芳基模块化修饰的影响提供了进一步的见解。
