Giannouli Vassiliki, Lougiakis Nikolaos, Kostakis Ioannis K, Pouli Nicole, Marakos Panagiotis, Skaltsounis Alexios-Leandros, Horne David A, Nam Sangkil, Gioti Katerina, Tenta Roxane
Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece.
Division of Pharmacognosy & Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece.
Med Chem. 2020;16(2):176-191. doi: 10.2174/1573406415666190222130225.
Purine isosteres are often endowed with interesting pharmacological properties, due to their involvement in cellular processes replacing the natural purines. Among these compounds, pyrazolopyridines are under active investigation for potential anticancer properties.
Based on previously discovered substituted pyrazolopyridines with promising antiproliferative activity, we designed and synthesized new, suitably substituted analogues aiming to investigate their potential activity and contribute to SAR studies of this class of bioactive compounds.
The new compounds were synthesized using suitably substituted 2-amino-4-picolines, which upon ring-closure provided substituted pyrazolo[3,4-c] pyridine-5-carbonitriles that served as key intermediates for the preparation of the target 3,5,7 trisubstituted derivatives. The antiproliferative activity of 31 new target derivatives was evaluated against three cancer cell lines (MIA PaCa-2, PC-3 and SCOV3), whereas cell-cycle perturbations of exponentially growing PC-3 cells, using three selected derivatives were also performed.
Eight compounds displayed IC50 values in the low μM range, allowing the extraction of interesting SAR's. Two of the most potent compounds against all cell lines share a common pattern, by accumulating cells at the G0/G1 phase. From this project, a new carboxamidine-substituted hit has emerged.
Among the new compounds, those possessing the 3-phenylpyrazolo[3,4-c]pyridine scaffold, proved to be worth investigating and the majority of them showed strong cytotoxic activity against all cell lines, with IC50 values ranging from 0.87-4.3 µM. A carboxamidine analogue that resulted from the synthetic procedure, proved to be highly active against the cancer cells and could be considered as a useful lead for further optimization.
嘌呤生物电子等排体由于参与取代天然嘌呤的细胞过程，常常具有有趣的药理特性。在这些化合物中，吡唑并吡啶因其潜在的抗癌特性而受到积极研究。
基于先前发现的具有良好抗增殖活性的取代吡唑并吡啶，我们设计并合成了新的、适当取代的类似物，旨在研究其潜在活性，并为这类生物活性化合物的构效关系研究做出贡献。
使用适当取代的2-氨基-4-甲基吡啶合成新化合物，环合后得到取代的吡唑并[3,4-c]吡啶-5-腈，作为制备目标3,5,7三取代衍生物的关键中间体。评估了31种新目标衍生物对三种癌细胞系（MIA PaCa-2、PC-3和SCOV3）的抗增殖活性，同时还使用三种选定的衍生物对指数生长的PC-3细胞进行了细胞周期扰动实验。
八种化合物的IC50值在低 microM 范围内，从中提取出了有趣的构效关系。对所有细胞系最具活性的两种化合物具有共同模式，即使细胞在G0/G1期积累。从该项目中出现了一种新的脒基取代的活性化合物。
在新化合物中，那些具有3-苯基吡唑并[3,4-c]吡啶骨架的化合物被证明值得研究，它们中的大多数对所有细胞系都表现出强烈的细胞毒性活性，IC50值范围为0.87 - 4.3 µM。合成过程中得到的一种脒基类似物对癌细胞具有高活性，可被视为进一步优化的有用先导化合物。
