Maccari Rosanna, Del Corso Antonella, Paoli Paolo, Adornato Ilenia, Lori Giulia, Balestri Francesco, Cappiello Mario, Naß Alexandra, Wolber Gerhard, Ottanà Rosaria
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Universitario Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
Department of Biology, Biochemistry Unit, University of Pisa, Via S. Zeno, 51, 56123 Pisa, Italy.
Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3712-3720. doi: 10.1016/j.bmcl.2018.10.024. Epub 2018 Oct 15.
Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1-17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.
设计的多配体（DMLs）旨在同时调节多种参与多因素疾病（如糖尿病，DM）发病机制的选定靶点，当单一疗法效果不理想时，被认为是药物组合的一种有前景的替代方案。在这项工作中，合成了化合物1 - 17，并对其作为针对醛糖还原酶（AR）和蛋白酪氨酸磷酸酶1B（PTP1B）的DMLs进行了体外评估，这两种关键酶参与了不同的事件，这些事件对2型糖尿病及其相关病理的发生和发展至关重要。在测试的4 - 噻唑烷酮衍生物中，化合物12和16表现出强大的AR抑制作用以及有趣的PTP1B抑制作用，可以被视为进一步优化和平衡双重抑制特性的先导化合物。此外，还确定了几个结构部分，这些特征可能有助于通过与两种靶酶的非催化区域结合来同时抑制人AR和PTP1B。
