title: Synthesis and biological evaluation of 2,4-diaminopyrimidines as selective Aurora A kinase inhibitors.
abstract: The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 μM. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Wen-Wen
authors: WW
authors: Qin
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Chun-Yan
authors: CY
authors: Sang
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Lin-Lin
authors: LL
authors: Zhang
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Wei
authors: W
authors: Wei
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Heng-Zhi
authors: HZ
authors: Tian
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors: Huan-Xiang
authors: HX
authors: Liu
authors: School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.
authors: Shi-Wu
authors: SW
authors: Chen
authors: Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China; Key Laboratory of Stem Cells and Gene Drug of Gansu Province, General Hospital of Lanzhou Military Command, Lanzhou 730050, China.
authors: Ling
authors: L
authors: Hui
mesh_terms: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry*; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D064096:Aurora Kinase A; D064107:Aurora Kinase B; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000604756:4-((5-bromo-4-(cyclopentylamino)-2-yl)amino)-N-(1-methylpiperidin-4-yl)benzamidepyrimidine; C017205:2,4-diaminopyrimidine; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles
keywords: Aurora kinase; Cell cycle; Kinase inhibitors; Pyrimidine