Ravish Akshay, Shivakumar Rashmi, Xi Zhang, Yang Min Hee, Yang Ji-Rui, Swamynayaka Ananda, Nagaraja Omantheswara, Madegowda Mahendra, Chinnathambi Arunachalam, Alharbi Sulaiman Ali, Pandey Vijay, Sethi Gautam, Ahn Kwang Seok, Lobie Peter E, Basappa Basappa
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
Shenzhen Bay Laboratory, Shenzhen 518055, China.
Bioengineering (Basel). 2023 Jan 24;10(2):159. doi: 10.3390/bioengineering10020159.
In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC.
在乳腺癌（BC）中，信号转导和转录激活因子3（STAT3）被过度激活。本研究探索了咪唑并吡啶连接的吡唑啉类化合物的设计，作为一种全新的药物策略，用于抑制人乳腺癌细胞中STAT3的磷酸化。这涉及到两个系列化合物的合成与表征，即1-(3-(2,6-二甲基咪唑并[1,2-a]吡啶-3-基)-5-(3-硝基苯基)-4,5-二氢-1H-吡唑-1-基)-2-(4-(取代)哌嗪-1-基)乙酮和N-取代-3-(2,6-二甲基咪唑并[1,2-a]吡啶-3-基)-5-(3-硝基苯基)-4,5-二氢-1H-吡唑啉-1-碳硫酰胺。在测试系列中，具有2,3-二氯苯基取代的化合物被认为是一种先导结构，其对MCF-7细胞活力的抑制IC值为9.2 μM。当在体外添加该化合物时，在MCF-7和T47D细胞中观察到了对Tyr705和Ser727位点STAT3磷酸化的剂量和时间依赖性抑制。使用密度泛函理论的计算表明，标题化合物的最高占据分子轨道（HOMOs）和最低未占据分子轨道（LUMOs）分别位于咪唑并吡啶-吡唑啉环和硝基苯环上。因此，该化合物有效抑制了MCF-7和T47D细胞中STAT3的磷酸化，表明这些结构可能是靶向乳腺癌中STAT3信号传导的一种替代合成子。
