Design and synthesis of 2-aryl-4-(trans-4-hydroxycyclohexanylamino)-5-ethyl- 7H-pyrrolo2, 3-dpyrimidines and Mer tyrosine kinase inhibitory activity evaluation / 国际药学研究杂志

ABSTRACT

Objective: To design and synthesize a series of 2-aryl-4-(trans-4-hydroxycyclohexanolamine)-7H-pyrrolo[2, 3-d] pyrimidine derivatives and test their inhibitory activity against Mer tyrosine kinase(MerTK)and tumor cell proliferation. Methods: 2, 4-Dichloro-7H-pyrrolo[2, 3-d]pyrimidine(1)was used as starting material to synthesize the target compounds via iodination, protection with p- Tosyl(Ts), nucleophilic substitution, Stille coupling, vinyl reduction, Suzuki coupling and deprotection of Ts. The MerTK inhibitory activity was tested by the Kinase-Glo Plus luminescence method. The antiproliferation activity was assayed using MV- 4-11, A549, MDA-MB-231, KB, and KB-vin tumor cell lines by the CCK8 and SRB methods. Molecular docking of MerTK and 6h was conducted using the DS3.0 software. Results: Nine compounds were synthesized, and their structures were confirmed by 1H NMR and MS. Compound 6h exhibited certain inhibitory effect on MerTK, with the(6.7±0.3)μmol/L of IC50 value, and could selectively inhibit the growth of MV-4-11 tumor cells, with the(6.6±1.1)μmol/L of GI50 value that was approximately 3-fold to 6-fold more potent than the GI50 value of 6h on the other tested tumor cells. Molecular docking showed that 6h could interact with MerTK on the binding site of UNC569 and overlapped well with the original ligand UNC569, but its binding energy was higher than the binding energy of UNC569. Conclusion: Compound 6h showed a selective inhibitory effect on the MV-4-11 cell growth, which might be further investigated via more biological experiments to explore whether the inhibitory effect is related to the inhibition of MerTK by 6h. The molecular docking results in the present study have suggested that further structural modification on the 2 and 5 position of 7H-pyrrolo[2, 3-d] pyrimidine skeleton could likely improve the MerTK inhibitory activity.