Department of Pharmaceutical chemistry, Faculty of Pharmacy, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania.
National Research and Development Institute for Cryogenics and Isotopic Technologies, ICSI Analytics, 4th Uzinei Street, RO-240050 Râmnicu Vâlcea, Romania.
Medicina (Kaunas). 2019 Mar 31;55(4):85. doi: 10.3390/medicina55040085.
Cancer represents the miscommunication between and within the body cells. The mutations of the oncogenes encoding the MAPK pathways play an important role in the development of tumoral diseases. The mutations of KRAS and BRAF oncogenes are involved in colorectal cancer and melanoma, while the NRAS mutations are associated with melanoma. Thiazolidine-2,4-dione is a versatile scaffold in medicinal chemistry and a useful tool in the development of new antitumoral compounds. The aim of our study was to predict the pharmacokinetic/pharmacodynamic properties, the drug-likeness and lead-likeness of two series of synthetic 5-arylidene(chromenyl-methylene)-thiazolidinediones, the molecular docking on the oncoproteins K-Ras, N-Ras and B-Raf, and to investigate the cytotoxicity of the compounds, in order to select the best structural profile for potential anticancer agents. In our paper we studied the cytotoxicity of two series of thiazolidine-2,4-dione derivatives, their ADME-Tox properties and the molecular docking on a mutant protein of K-Ras, two isoforms of N-Ras and an isoform of B-Raf with 16 mutations. The heterocyclic compounds strongly interact with K-Ras and N-Ras right after their posttranslational processing and/or compete with GDP for the nucleotide-binding site of the two GTPases. They are less active against the GDP-bound states of the two targets. All derivatives have a similar binding pattern in the active site of B-Raf. The data obtained encourage the further investigation of the 5-arylidene(chromenyl-methylene)-thiazolidinediones as potential new agents against the oncoproteins K-Ras, N-Ras and B-Raf.
癌症代表了体内细胞之间和细胞内部的通讯错误。编码 MAPK 通路的癌基因的突变在肿瘤疾病的发展中起着重要作用。KRAS 和 BRAF 癌基因的突变涉及结直肠癌和黑色素瘤，而 NRAS 突变与黑色素瘤有关。噻唑烷-2,4-二酮是药物化学中的多功能支架，是开发新的抗肿瘤化合物的有用工具。我们的研究目的是预测两个系列合成的 5-芳亚基（色烯亚甲基）-噻唑烷-2,4-二酮的药代动力学/药效学特性、药物相似性和先导相似性，对致癌蛋白 K-Ras、N-Ras 和 B-Raf 进行分子对接，并研究化合物的细胞毒性，以选择最佳的结构特征，作为潜在的抗癌药物。在我们的论文中，我们研究了两个系列噻唑烷-2,4-二酮衍生物的细胞毒性、它们的 ADME-Tox 特性以及对 K-Ras 突变体蛋白、两种 N-Ras 同工型和一种带有 16 个突变的 B-Raf 同工型的分子对接。杂环化合物在 K-Ras 和 N-Ras 翻译后加工后立即与它们强烈相互作用，并且与 GDP 竞争两种 GTPase 的核苷酸结合位点。它们对两种靶标 GDP 结合状态的活性较低。所有衍生物在 B-Raf 的活性位点具有相似的结合模式。获得的数据鼓励进一步研究 5-芳亚基（色烯亚甲基）-噻唑烷-2,4-二酮作为针对致癌蛋白 K-Ras、N-Ras 和 B-Raf 的潜在新药物。
