Department of Chemistry, University of Patras, 26504 Rion, Greece.
Department of Pharmacology, School of Medicine, University of Crete, 71003 Heraklion, Greece.
Int J Mol Sci. 2023 Oct 16;24(20):15232. doi: 10.3390/ijms242015232.
Gonadotropin-releasing hormone (GnRH) is pivotal in regulating human reproduction and fertility through its specific receptors. Among these, gonadotropin-releasing hormone receptor type I (GnRHR I), which is a member of the G-protein-coupled receptor family, is expressed on the surface of both healthy and malignant cells. Its presence in cancer cells has positioned this receptor as a primary target for the development of novel anti-cancer agents. Moreover, the extensive regulatory functions of GnRH have underscored decapeptide as a prominent vehicle for targeted drug delivery, which is accomplished through the design of appropriate conjugates. On this basis, a rationally designed series of anthraquinone/mitoxantrone-GnRH conjugates (-) has been synthesized herein. Their in vitro binding affinities range from 0.06 to 3.42 nM, with six of them (-) demonstrating higher affinities for GnRH than the established drug leuprolide (0.64 nM). Among the mitoxantrone based GnRH conjugates, and show the highest affinities at 0.07 and 0.06 nM, respectively, while the disulfide bond present in the conjugates is found to be readily reduced by the thioredoxin (Trx) system. These findings are promising for further pharmacological evaluation of the synthesized conjugates with the prospect of performing future clinical studies.
促性腺激素释放激素（GnRH）通过其特异性受体在调节人类生殖和生育中起着关键作用。在这些受体中，促性腺激素释放激素受体 1 型（GnRHR1）是 G 蛋白偶联受体家族的成员，在健康细胞和恶性细胞的表面均有表达。其在癌细胞中的存在使该受体成为开发新型抗癌药物的主要靶点。此外，GnRH 的广泛调节功能强调了十肽作为靶向药物递送的突出载体，这是通过设计适当的缀合物来实现的。在此基础上，本文设计并合成了一系列具有合理结构的蒽醌/米托蒽醌-GnRH 缀合物（-）。它们的体外结合亲和力范围为 0.06 到 3.42 nM，其中 6 个缀合物（-）对 GnRH 的亲和力高于已上市药物亮丙瑞林（0.64 nM）。在米托蒽醌基 GnRH 缀合物中，和分别具有 0.07 和 0.06 nM 的最高亲和力，而缀合物中存在的二硫键被发现可被硫氧还蛋白（Trx）系统容易还原。这些发现为进一步对合成缀合物进行药理学评价提供了希望，并有望开展未来的临床研究。
