CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta Apolónia, Apartado 1172, 5301-855 Bragança, Portugal.
Eur J Med Chem. 2011 Dec;46(12):5800-6. doi: 10.1016/j.ejmech.2011.09.029. Epub 2011 Oct 6.
Hepatocellular carcinoma (HCC) is a highly complex cancer, resistant to commonly used treatments and new therapeutic agents are urgently needed. A total of thirty-two thieno[3,2-b]pyridine derivatives of two series: methyl 3-amino-6-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates (1a-1t) and methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates (2a-2n), previously prepared by some of us, were evaluated as new potential anti-HCC agents by studying their in vitro cell growth inhibition on human HepG2 cells and hepatotoxicity using a porcine liver primary cell culture (PLP1). The presence of amino groups linked to a benzene moiety emerges as the key element for the anti-HCC activity. The methyl 3-amino-6-[(3-aminophenyl)ethynyl]thieno[3,2-b]pyridine-2-carboxylate (2f) is the most potent compound presenting GI(50) values on HepG2 cells of 1.2 μM compared to 2.9 μM of the positive control ellipticine, with no observed hepatotoxicity (PLP1 GI(50) > 125 μM against 3.3 μM of ellipticine). Moreover this compound changes the cell cycle profile of the HepG2 cells, causing a decrease in the % of cells in the S phase and a cell cycle arrest in the G2/M phase. QSAR studies were also performed and the correlations obtained using molecular and 1D descriptors revealed the importance of the presence of amino groups and hydrogen bond donors for anti-HCC activity, and hydrogen bond acceptors for hepatotoxicity. The best correlations were obtained with 3D descriptors belonging to different subcategories for anti-HCC activity and hepatotoxicity, respectively. These results point to different molecular mechanisms of action of the compounds in anti-HCC activity and hepatotoxicity. This work presents some promising thieno[3,2-b]pyridine derivatives for potential use in the therapy of HCC. These compounds can also be used as scaffolds for further synthesis of more potent analogs.
肝细胞癌（HCC）是一种高度复杂的癌症，对常用治疗方法具有耐药性，因此急需新的治疗药物。本研究共合成了两个系列的 32 种噻吩并[3,2-b]吡啶衍生物：3-氨基-6-（杂环）芳基噻吩并[3,2-b]吡啶-2-羧酸甲酯（1a-1t）和 3-氨基-6-[(杂环)芳基乙炔基]噻吩并[3,2-b]吡啶-2-羧酸甲酯（2a-2n），这些化合物是由我们中的一些人以前制备的，通过研究它们对人肝癌 HepG2 细胞的体外细胞生长抑制作用以及使用猪原代肝细胞培养物（PLP1）的肝毒性，评估它们作为新型潜在的抗 HCC 药物的潜力。与苯环相连的氨基的存在是抗 HCC 活性的关键因素。3-氨基-6-[(3-氨基苯基)乙炔基]噻吩并[3,2-b]吡啶-2-羧酸甲酯（2f）是最有效的化合物，在 HepG2 细胞中的 GI（50）值为 1.2 μM，而阳性对照药椭圆体素的 GI（50）值为 2.9 μM，且无肝毒性（PLP1 GI（50）> 125 μM，而椭圆体素的 GI（50）值为 3.3 μM）。此外，该化合物改变了 HepG2 细胞的细胞周期谱，导致 S 期细胞比例降低，G2/M 期细胞周期停滞。还进行了 QSAR 研究，使用分子和 1D 描述符获得的相关性表明，氨基和氢键供体的存在对 HCC 活性很重要，而氢键受体对肝毒性很重要。对于抗 HCC 活性和肝毒性，分别获得了与 3D 描述符的最佳相关性，这些描述符属于不同的子类别。这些结果表明，化合物在抗 HCC 活性和肝毒性方面具有不同的分子作用机制。本工作提出了一些有前途的噻吩并[3,2-b]吡啶衍生物，可用于 HCC 的治疗。这些化合物还可以用作进一步合成更有效类似物的支架。
