Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
Eur J Med Chem. 2014 Aug 18;83:1-14. doi: 10.1016/j.ejmech.2014.06.017. Epub 2014 Jun 10.
A new series of pseudopeptide boronate proteasome inhibitors (2-3) was developed, through optimization of our previously described analogs of bortezomib, bearing a bicyclic 1,6-naphthyridin-5(6H)-one scaffold as P3 fragment (1). The biological evaluation on human 20S proteasome displayed a promising inhibition profile, especially for compounds bearing a P2 ethylene fragment, which exhibited Ki values in the nanomolar range for the ChT-L activity (e.g. 2a, Ki = 0.057 μM) and considerable selectivity for proteasome over bovine pancreatic α-chymotrypsin. Docking experiments into the yeast 20S proteasome revealed that the ligands are accommodated predominantly into the ChT-L site and that they covalently bind to the active site threonine residue via boron atom. Within the cellular assays performed against a 60 cancer cell line panel, compounds 3e and 3f demonstrated also good antiproliferative activity and compound 3f emerged as promising lead compound for the development of anticancer agents targeting melanoma and non-small cell lung cancer.
我们开发了一系列新的硼酸蛋白酶体抑制剂伪肽（2-3），通过对我们以前描述的硼替佐米类似物进行优化，这些类似物具有双环 1,6-萘啶-5(6H)-酮作为 P3 片段（1）。对人 20S 蛋白酶体的生物学评估显示出有希望的抑制谱，特别是对于具有 P2 亚乙基片段的化合物，其对 ChT-L 活性的 Ki 值在纳摩尔范围内（例如 2a，Ki = 0.057 μM），并且对蛋白酶体具有相当的选择性，而对牛胰腺α-糜蛋白酶则没有选择性。对接实验表明，配体主要容纳在 ChT-L 位点，并且通过硼原子与活性位点苏氨酸残基共价结合。在针对 60 个癌细胞系panel 的细胞测定中，化合物 3e 和 3f 也表现出良好的增殖抑制活性，化合物 3f 作为针对黑色素瘤和非小细胞肺癌的抗癌药物开发的有前途的先导化合物脱颖而出。
