Amărandi Roxana-Maria, Al-Matarneh Maria-Cristina, Popovici Lăcrămioara, Ciobanu Catalina Ionica, Neamțu Andrei, Mangalagiu Ionel I, Danac Ramona
TRANSCEND Research Center, Regional Institute of Oncology Iasi, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania.
"Petru Poni" Institute of Macromolecular Chemistry of Romanian Academy, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania.
Pharmaceuticals (Basel). 2023 Jun 11;16(6):865. doi: 10.3390/ph16060865.
Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-]quinoline was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound , docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective.
通过支架杂交策略设计了五个新的吡咯并稠合杂环系列，作为著名的微管抑制剂苯抑素的类似物。以环亚胺N-叶立德与丙炔酸乙酯的1,3-偶极环加成反应为关键步骤合成化合物。然后对所选化合物进行体外抗癌活性和抑制微管蛋白聚合能力的评估。值得注意的是，吡咯并[1,2 -]喹啉对大多数测试细胞系具有活性，在几种情况下表现优于对照苯抑素，最显著的是对肾癌细胞系A498（GI 27 nM），同时在体外抑制微管蛋白聚合。此外，预计该化合物具有良好的药物代谢动力学性质。通过计算机对接实验，随后进行分子动力学模拟和构型熵计算，研究了该化合物与微管蛋白之间相互作用的分子细节。值得注意的是，我们发现对接实验最初预测的一些相互作用在分子动力学模拟过程中不稳定，但在所有三种情况下构型熵损失相似。我们的结果表明，对于该化合物，仅靠对接实验不足以充分描述靶点结合方面的相互作用细节，这使得后续的支架优化更加困难，最终阻碍药物设计。综上所述，这些结果有助于设计具有吡咯并稠合杂环核心的新型强效抗增殖化合物，特别是从计算机方法学的角度。
