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

• Published in: Dalton transactions : an international journal of inorganic chemistry 2019-12, Vol.48 (47), p.17673-17682
• Main Authors: Lin, Lixia, Lu, Liping, Du, Ran, Yuan, Caixia, Zhu, Miaoli, Fu, Xueqi, Xing, Shu
• Format: Article
• Language: English
• Subjects: A549 Cells; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cerium - chemistry; Cerium - pharmacology; Chemical analysis; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystallography; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluorescence; Humans; Imines; Infrared analysis; Ligands; Models, Molecular; Molecular Structure; Mopping; Phosphatase; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Schiff Bases - chemical synthesis; Schiff Bases - chemistry; Schiff Bases - pharmacology; Selectivity; Single crystals; Structure-Activity Relationship; Substrate inhibition; Tyrosine
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c9dt03200b

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 (NO 3 ) 3 ]·2CH 3 OH ( 1 ), [Ce(L2) 2 (NO 3 )]·3H 2 O ( 2 ), [Ce(HL3)(L3)(NO 3 )Br]·H 2 O ( 3 ) and [Ce(L4) 2 (NO 3 )]·3H 2 O ( 4 ), in which ligands HL1-HL4 are respectively N ′-[(1 E )-pyridin-2-ylmethylidene]pyrazine-2-carbohydrazide (HL1), 2-(1-(salicyloylhydrazono)ethyl)pyrazine (HL2), N ′-[(1 E )-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 IC 50 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 × 10 5 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. Complex 3 potently inhibits the activity and expression of tyrosine phosphatase SHP-2 and decreases cellular viability.