A Ce(iii) complex potently inhibits the activity and expression of tyrosine phosphatase SHP-2

Abstract

Four new Ce(III) complexes 1–4 with tridentate NNO-donor Schiff base ligands have been designed and successfully synthesized. These complexes were characterized by elemental analysis, IR, and ESI-MS, with formulas of [Ce(HL1)₂(NO₃)₃]·2CH₃OH (1), [Ce(L2)₂(NO₃)]·3H₂O (2), [Ce(HL3)(L3)(NO₃)Br]·H₂O (3) and [Ce(L4)₂(NO₃)]·3H₂O (4), in which ligands HL1–HL4 are respectively N′-[(1E)-pyridin-2-ylmethylidene]pyrazine-2-carbohydrazide (HL1), 2-(1-(salicyloylhydrazono)ethyl)pyrazine (HL2), N′-[(1E)-pyridin-2-ylmethylidene]pyridine-2-carbohydrazide (HL3) and 2-(1-(salicyloylhydrazono)ethyl) pyridine (HL4). X-ray single crystal diffraction analysis indicates that complex 1 crystallizes in the monoclinic system with the space group C_2/c and the structure of complex 1 consists of a monomeric Ce(III) species with a Ce(III) moiety bonded to two tridentate Schiff base ligands, three nitrates and solvents. These complexes effectively inhibit the enzyme activities of PTPs (SHP-1, SHP-2, TCPTP and PTP1B), among which complex 3 shows the most potent inhibition of SHP-2 with the lowest IC₅₀ value of 0.61 μM and displays obvious selectivity towards SHP-2. Its inhibition potency against SHP-2 was approximately 17, 4, and 5 fold higher than that against SHP-1, TCPTP and PTP1B, respectively. Further study discloses that complex 3 inhibits SHP-2 in a competitive manner. Fluorescence measurements indicate that complex 3 tightly binds to SHP-2 with a molar ratio of 1 : 1 and a binding constant of 5.45 × 10⁵ M⁻¹. Western blot experiments show that complex 3 promotes the phosphorylation of the SHP-2 substrate by the combination of the inhibition of the activity and expression of SHP-2. Moreover, complex 3 decreases the survival rate of A549 cells to 35.12% at 100 μM and induces apoptosis with an apoptosis rate of 12.06% at 50 μM. All these results suggest that complex 3 is a potential bi-functional inhibitor of the activity and expression of tyrosine phosphatase SHP-2.