Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow,Russian Federation.
Curr Med Chem. 2022;29(2):268-298. doi: 10.2174/0929867328666210804092200.
Cancer is one of the leading social problems of the modern world. Today prostate cancer is the second leading cause of cancer deaths among men. Targeted drug delivery is widely used to treat and diagnose prostate cancer. Conjugates selectively binding to prostatespecific membrane antigen-based on urea ligands are being actively developed against this disease. The linker has a significant influence on the biological activity of such conjugates. The linker performs a large number of functions, and its modification is one of the key methods for creating the best pharmacological profile. This review aims to discuss and analyze the main approaches to the method of introduction and synthesis of linkers for this type of conjugates without a description of the influence of biologically active molecules, as well as to establish the key modification methods that have a significant role on the structure-activity relationship. For this purpose, a review of the current scientific literature was performed, both for the conjugates under development and those already undergoing clinical trials. It was found that the optimal structure is a linker containing an aliphatic fragment near the vector- molecule (n(CH2) = 3-6), followed by a polypeptide chain consisting of 2 to 4 amino acid residues. The presence of a Phe-Phe dipeptide chain or the introduction of negatively charged groups also has a positive effect. Ongoing research in this field helps to establish the accurate effect of each linker fragment, and the development of solid-phase synthesis methods makes it much easier to achieve this goal.
癌症是现代世界主要的社会问题之一。如今，前列腺癌是男性癌症死亡的第二大主要原因。靶向药物输送被广泛用于治疗和诊断前列腺癌。基于尿素配体选择性结合前列腺特异性膜抗原的缀合物正在积极开发用于治疗这种疾病。接头对这类缀合物的生物活性有重要影响。接头具有多种功能，其修饰是创造最佳药理学特性的关键方法之一。本综述旨在讨论和分析用于此类缀合物的接头引入和合成方法的主要方法，而不描述生物活性分子的影响，以及建立对结构-活性关系具有重要作用的关键修饰方法。为此，对正在开发和已经进行临床试验的缀合物进行了当前科学文献的综述。结果发现，最佳结构是在载体分子附近含有脂肪族片段的接头(n(CH2) = 3-6)，然后是由 2 到 4 个氨基酸残基组成的多肽链。存在苯丙氨酸-苯丙氨酸二肽链或引入带负电荷的基团也有积极的影响。该领域的正在进行的研究有助于确定每个接头片段的准确效果，并且固相合成方法的发展使其更容易实现这一目标。
