Design and synthesis of novel dasatinib derivatives as inhibitors of leukemia stem cells

Bioorg Med Chem Lett. 2018 Feb 15;28(4):700-706. doi: 10.1016/j.bmcl.2018.01.011.

Hui-Ying Li ¹, Ding-Di He ², Xiu-Juan Zhao ², Tong-Yan Sun ², Quan Zhang ³, Cui-Gai Bai ⁴, Yue Chen ⁵

Affiliations

1 High-throughput Molecular Drug Discovery Center, Tianjin international Joint Academy of BioMedicine, Tianjin 300457, PR China.
2 The State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, PR China; High-throughput Molecular Drug Discovery Center, Tianjin international Joint Academy of BioMedicine, Tianjin 300457, PR China.
3 The State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, PR China.
4 High-throughput Molecular Drug Discovery Center, Tianjin international Joint Academy of BioMedicine, Tianjin 300457, PR China. Electronic address: [email protected].
5 The State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, PR China. Electronic address: [email protected].

PMID: 29395973 DOI: 10.1016/j.bmcl.2018.01.011

Abstract

We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC₅₀ = 0.039 nM vs. 0.069 nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC₅₀ = 0.25 nM and 0.26 nM vs. 0.11 nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d-15f and oxadiazole compounds 24a-24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC₅₀ = 0.14 μM and 0.05 μM vs. 8.98 μM). Compounds 15a and 24a also inhibited colony formation in MCF-7 cells and inhibited cell migration in the cell wound scratch assay in B16BL6 cells. Moreover, hydroxyl compounds 15a and 24a had low toxicity in vivo.

Keywords

Bioisosteres; Cell migration; Colony formation; Dasatinib derivatives; Oxadiazole; Triazole.

Name
Email *

	Sorry, but the email address you supplied was invalid.