Lipophilic prodrugs of oligonucleotides: synthesis, properties and conjugates for cellular targeting

寡核苷酸（ON）是有吸引力的候选药物，因为它们显示出以序列特异性方式结合内源性核酸的潜力。因此，单链ON可以通过反义机制（即通过序列特异性结合mRNA）抑制蛋白质的生物合成，从而导致基因产物的选择性调节。然而，ON的潜在治疗应用受到重大障碍的阻碍。特别是，它们的药代动力学性质（细胞摄取和稳定性）不足，因此需要对ON的主链结构进行化学修饰。这导致了大量已经描述过的这样的主干修饰。尽管在这一领域取得了一些显著的成功，但这些修饰都没有成为一种普遍适用的工具，用于药理上有用的ON结构的改变。基于这些原因，讨论了ON的前药概念设计，以改善其药代动力学特性。因此，ON的极性聚阴离子主链被亲脂性单元“掩盖”，亲脂性单元在细胞摄取后被切割以提供ON（“化学特洛伊木马”原理）。在本项目中，我们的目标是开发和研究具有潜在反义活性的单链ON的新型前药。因此，预计它将从根本上促进具有治疗潜力的改性ON的发展。将建立新的ON前药的合成，并对相应的产品进行详细的药代动力学特性测试。此外，我们的目标是建立这种ON前药的细胞靶向性，以便将它们开发成治疗上有用的反义药物。因此，我们将研究一种针对雌激素依赖性乳腺癌细胞的细胞特异性靶向的新方法，该方法基于低分子靶向单位与on前药的偶联。总体目标将是获得一种ON前药作为潜在的候选药物，具有抗乳腺癌细胞的活性。

Oligonucleotides (ON) represent attractive drug candidates as they display the potential to bind endogenous nucleic acids in a sequence-specific manner. Thus, single-stranded ON can inhibit protein biosynthesis via the antisense mechanism (i.e. via sequence-specific binding to mRNA), resulting in the selective modulation of a gene product. However, potential therapeutic applications of ON are hampered by significant hurdles. In particular, their pharmacokinetic properties (cellular uptake and stability) are insufficient, hence requiring the chemical modification of the backbone structure of ON. This has resulted in a significant number of such backbone modifications which have already been described. In spite of some remarkable success in this field, none of these modifications has become a universally applicable tool for a pharmacologically useful alteration of ON structures. For these reasons, the design of prodrug concepts for ON has been discussed in order to improve their pharmacokinetic properties. Thus, the polar polyanionic backbone of ON is envisioned to be 'masked' with lipophilic units, which are supposed to be cleaved after cellular uptake to provide the ON ('chemical Trojan horse' principle). In this project, we aim to develop and investigate novel prodrugs of single-stranded ON with potential antisense activity. Thereby, it is envisioned to fundamentally contribute to the development of modified ON with therapeutic potential. The synthesis of new ON prodrugs will be established, and the according products will be tested in detail for their pharmacokinetic properties. Furthermore, it is our goal to establish the cellular targeting of such ON prodrugs in order to develop them into therapeutically useful antisense agents. We will therefore study a novel approach for a cell-specific targeting of estrogen-dependent breast cancer cells, which is based on the conjugation of low-molecular targeting units with the ON prodrugs. The overall goal will be to obtain an ON prodrug as a potential drug candidate with activity against breast cancer cells.