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The Study on Synthesis and Anti-tumor Activity of Mimics of Manganese Superoxide Dismutase

Author: AnZuo
Tutor: WeiHuLai
School: Lanzhou University
Course: Biochemistry and Molecular Biology
Keywords: MnSOD mimetic compounds Synthesis Leukemia Gastric cancer Hepatic carcinoma The anti-tumor activity Apoptosis ROS Bcl-2
CLC: R730.5
Type: Master's thesis
Year: 2007
Downloads: 81
Quote: 1
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Abstract


Objective: To study the manganese superoxide dismutase mimetic compounds (Mimics the best choice of manganese superoxide dismutase of MnSOD m ), synthetic and human leukemia cells and solid tumor cell anti-tumor effect and to explore of MnSOD m the molecular mechanism of anti-tumor effect. Method: synthesis of common synthetic method in accordance with the Schiff base with dual-core structure of MnSOD ligand and its complexes matter-of MnSOD m -1, -2 of MnSOD m and MnSOD m -3, and mass spectrometry, infrared spectroscopy characterization and single crystal structure analysis. Sensitive cells in human leukemia K562 cells, leukemia resistant cells K562/ADM cells SGC7901 gastric cancer cells and hepatoma HepG2 cells as target cells, application tetrazolium colorimetric the (MTF Law) Determination of cell proliferation activity; Annexin V / PI double notation detection K562/ADM cell apoptosis; optical microscopy, fluorescence microscopy and transmission electron microscopy to observe changes in cell morphology; the application flow cytometry (FCM), determination of K562/ADM cells Bcl-2 protein expression levels and intracellular ROS level. Results: the ① synthesis of MnSOD m nature stability, small molecular weight, easy transmembrane better water-soluble and fat-soluble, with dual-core structure in a complex molecule containing two manganese active center, increasing the same active concentration of a point having a higher activity. The ② synthesis of three of MnSOD m a dose-and time-dependent manner to inhibit proliferation of K562 cells of K562/ADM cells, SGC7901 cells and the proliferation of HepG2 cells (P <0.05). Which, of MnSOD , m -1 (in C 40 Mn the H 63 Cl 3 2 N 6 O 16 ) of K562 cells 24h, 48h, 72h of IC 50 respectively for 10.712mg / L, 1.138 mg / L and 0.618 mg / L, K562/ADM cells 24h, 48h, 72h of IC 50 respectively, for 22.410mg / L, 8.450 mg / L and 14.307mg / L, SGC7901 cells, 24h, 48h, and 72h IC 50 to 1.145mg / L, 2.266 mg / L and 7.388mg / L, HepG2 cells 24h, 48h and 72h IC 50 were 3.315mg / L , 12.515mg / L and 27.235mg / L; of MnSOD m -2 (in C 40 the H 48 Br 4 Mn 2 N 6 O 10 ) the K562 cells 24h, 48h, 72h of IC 50 were 32.111mG / L, 1.109mg / L and 0.587mg / L K562/ADM cells 224h, 48h and 72h IC 50 for 27.107mg / L, 9.051 mg / L and 4.216mg / L, on the SGC7901 Cell 24h, 48h and 72h of IC 50 to 1.139mg / L, 2.251 mg / L and 9.029mg / L, of HepG2 cells 24h, 48h and 72h of IC to 50 < / sub> to 1.682mg / L, 14.728 mg / L and 17.421mg / L; of MnSOD m -3 (C 40 H 57 Mn 2 N 9 O 21 ) of K562 cells 24h, 48h, 72h of IC 50 were 4.492mg / L, 0.815mg / L, and 10.422mg / L, to K562/ADM cells 24h, 48h, 72h of IC 50 were 23.969mg / L, 9.966mg / L and 3.611mg / L, SGC7901 cells 24h of 48h and 72h IC 50 1.238mg / L, 1.767mg / L and 4.223mg / L, of HepG2 cells 24h, 48h and 72h of IC to 50 < / sub> respectively, 4.818mg / L, 18.13mg / L and 28.786mg / L,. Confirmed that MnSOD mimetic compounds on leukemia cells, gastric cancer cells and liver cancer cells with strong anti-tumor activity MnSODm-3 effect; highest sensitivity of leukemia cells MnSOD complexes, followed by gastric cancer cells, liver cancer cells worst , and exhibits a certain resistance. The the ③ K562/ADM cells of MnSOD m -3 after induction, cell membrane blistering, chromatin condensation, pyknosis gathered to the nuclear membrane surrounding the crescent-shaped, nuclear fragmentation, apoptotic bodies (Apoptotic bodies) formed the typical morphological changes of apoptosis; Annexin V / PI double staining of apoptotic cells was significantly higher, 10 mg / L and 50mg / L of MnSOD m -3 handle K562/ADM cells 48h, the apoptosis rate of 13.9% and 55.0%, respectively. 10mg / L and 50mg / L of MnSOD m -3 role K562/ADM cells after 48h, the expression of intracellular ROS levels were significantly increased, ROS positive expression rate of increase of 61.0% to 95.8% and 98.6% ; but no significant changes in Bcl-2 protein expression levels. Prompted MnSOD m inhibition of leukemia (cancer) cell proliferation mechanism for the induction of apoptosis, the molecular mechanism of induction of apoptosis may be unrelated to the Bcl-2 intracellular ROS generation . Conclusion: We successfully synthesized the MnSOD mimetic compounds with dual-core structure; MnSOD m significantly inhibited the in vitro proliferation of leukemic cells and solid tumor cells, has a strong anti-tumor activity, and the mechanism for the induction of leukemia ( apoptosis of the tumor); MnSOD m -induced leukemia (tumor) may be related to increased apoptosis related to the level of intracellular ROS.

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