Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126, Pisa, Italy.
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134, Florence, Italy.
Biometals. 2023 Oct;36(5):961-968. doi: 10.1007/s10534-023-00496-8. Epub 2023 Mar 4.
Auranofin (1-(thio-κS)-β-D-glucopyranose-2,3,4,6-tetraacetato-gold) is a leading gold-based drug clinically used to treat arthritis. In the last years, it entered various drug reprofiling programs, and it has been found promising against various forms of tumor, including ovarian cancer. Evidence showed as its antiproliferative profile mainly depends on the inhibition of thioredoxin reductase (TrxR), being this mitochondrial system its main target. In this context, we report here the synthesis and biological evaluation of a novel complex designed as auranofin analogue obtained through the conjugation of a phenylindolylglyoxylamide ligand (which belongs to the so-called PIGA TSPO ligand family) with the auranofin-derived cationic fragment [Au(PEt)]. This complex is characterized by two parts. The phenylindolylglyoxylamide moiety, owing to its high affinity for TSPO (in the low nM range) should drive the compound to target mitochondria, whereas the [Au(PEt)] cation is the actual anticancer-active molecular fragment. Overall, we wanted to offer the proof-of-concept that by coupling PIGA ligands to anticancer gold active moieties, it is possible to preserve and even improve anticancer effects, opening the avenue to a reliable approach for targeted therapy.
金诺芬(1-(硫代-κS)-β-D-吡喃葡萄糖-2,3,4,6-四乙酸酯金)是一种临床用于治疗关节炎的主要金基药物。近年来，它进入了各种药物再利用计划，并被发现对各种形式的肿瘤有希望，包括卵巢癌。证据表明，其抗增殖作用主要取决于硫氧还蛋白还原酶(TrxR)的抑制，而该线粒体系统是其主要靶点。在这方面，我们在这里报告了一种新型配合物的合成和生物学评价，该配合物设计为金诺芬类似物，通过将苯并吲哚基甘氨酰酰胺配体(属于所谓的 PIGA TSPO 配体家族)与金诺芬衍生的阳离子片段[Au(PEt)]连接而获得。该配合物具有两个部分。苯并吲哚基甘氨酰酰胺部分，由于其与 TSPO 具有高亲和力(在低 nM 范围内)，应该使化合物靶向线粒体，而[Au(PEt)]阳离子是实际的抗癌活性分子片段。总的来说，我们希望证明这样一个概念，即通过将 PIGA 配体与抗癌金活性片段结合，可以保留甚至改善抗癌效果，为靶向治疗开辟一条可靠的途径。
