Demange, Luc; Abdellah, Fatma Nait; Lozach, Olivier; Ferandin, Yoan; Gresh, Nohad; Meijer, Laurent; Galons, Herve published the artcile< Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling>, Formula: C4H5N3, the main research area is isopropyl hydroxyalkylamino arylamino purine preparation roscovitine analog CDK5 inhibitor; structure isopropyl hydroxyalkylamino arylamino purine inhibition CDK5 DYRK1A kinase; mol docking energetics isopropyl hydroxyalkylamino arylamino purine binding CDK5; cell death induction CDK5 inhibiting isopropyl hydroxyalkylamino arylamino purine.
9-Isopropyl-2-(hydroxyalkylamino)-6-(arylamino)purines I [R = 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 4-pyridazinyl; R1 = Cl, (R)-Et(HOCH2)CHNH, (S)-Et(HOCH2)CHNH, (R)-Me2CH(HOCH2)CHNH, (S)-Me2CH(HOCH2)CHNH, (HOCH2)2CH, HOCH2CMe2NH, 5-pyrimidinylamino, 2-pyrazinylamino] were prepared as analogs of the CDK inhibitor roscovitine for potential use as selective inhibitors of cyclin-dependent kinase 5 (CDK5) over CDK2, glycogen synthase kinase-3 (GSK3αβ), and casein kinase 1 (CK1). Regioselective alkylation of 2,6-dichloropurine, regioselective Buchwald-Hartwig amination with arylamines, and reaction with amino alcs. yielded I, with chlorides generated by omission of the reaction with amino alcs., and I (R = R1 = 5-pyrimidinylamino, 2-pyrazinylamino) generated as diamination byproducts from Buchwald-Hartwig amination. I [R = 3-pyridinyl, 4-pyridinyl, 5-pyrimidinyl, 4-pyridazinyl; R1 = (R)-Et(HOCH2)CHNH, (S)-Et(HOCH2)CHNH, (R)-Me2CH(HOCH2)CHNH] inhibited CDK5 with IC50 values ranging from 17 to 50 nM and induced cell death in human neuroblastoma cells with IC50 values ranging from 2 to 9 μM in SH-SY5Y cells. Mol. docking of I [R = 4-pyrimidinyl; R1 = (R)-Et(HOCH2)CHNH] and I [R = 4-pyridazinyl; R1 = (R)-Et(HOCH2)CHNH] into the ATP binding domain of the CDK5 catalytic site highlighted the importance of a hydrogen bond between the arylamino ring nitrogen atoms and residue Lys-89 of CDK5 for enzyme inhibition. The calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC50 values. I [R = 3-pyridinyl, 5-pyrimidinyl; R1 = (R)-Me2CH(HOCH2)CHNH, (S)-Me2CH(HOCH2)CHNH] inhibited dual specificity, tyrosine phosphorylation regulated kinase 1A (DYRK1A), a kinase involved in Down’s syndrome and Alzheimer’s disease, with IC50 values ranging from 300 to 400 nM.
Bioorganic & Medicinal Chemistry Letters published new progress about Cell death. 20744-39-2 belongs to class pyridazine, and the molecular formula is C4H5N3, Formula: C4H5N3.
Referemce:
Pyridazine – Wikipedia,
Pyridazine | C4H4N2 – PubChem