- Low-oxygen activation AGT protein inhibitor and preparation method and application thereof
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The invention provides a low-oxygen activation AGT protein inhibitor shown in the general formula (I) (please see the formula in the description) and a preparation method and application thereof. In the formula, R1=R2=H or R1=H and R2=CH3 or R1=R2=CH3 and R3=H, NO2, OCH3, CH2OH or CO2CH3. The composition has a good low-oxygen activation characteristic and good tumor cell targeting performance, can inhibit the activity of AGT in solid tumors in the low-oxygen environment in a targeted mode, and improves the sensitivity of tumor cells to chemotherapy medicine. The composition has an obvious inhibition function on various solid tumor cell systems when used together with ACNU, can obviously improve the sensitivity of tumor cells to anti-cancer medicine when used together with alkylating agent type anti-cancer medicine, and can be used for targeted combined chemotherapy of malignant tumors.
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Paragraph 0056-0061; 0081-0086; 0106-0111; 0131-0136; 0156
(2017/05/27)
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- Monosaccharide-linked inhibitors of O6-methylguanine-DNA methyltransferase (MGMT): Synthesis, molecular modeling, and structure-activity relationships
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A series of potential inhibitors of the human DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) were synthesized, characterized in detail by NMR, and tested for their ability to deplete MGMT activity in vitro. The new compounds, ω-[O6-R-guan-9-yl]-(CH2)n-β-d- glucosides with R = benzyl or 4-bromothenyl and ω = n = 2, 4, ... 12, were compared with the established inhibitors O6-benzylguanine (O6-BG), 8-aza-O6-benzylguanine (8-aza-BG), and O6-(4-bromothenyl)guanine (4-BTG), which exhibit in an in vitro assay IC50 values of 0.62, 0.038, and 0.009 μM, respectively. Potential advantages of the glucosides are improved water solubility and selective uptake in tumor cells. The 4-BTG glucosides with n = 2, 4, 6 show moderate inhibition with an IC50 of ca. 0.5 μM, while glucosides derived from BG and 8-aza-BG showed significantly poorer inhibition compared to the parent compounds. The 4-BTG glucosides with n = 8, 10, 12 were effective inhibitors with IC50 values of ca. 0.03 μM. To understand this behavior, extensive molecular modeling studies were performed using the published crystal structure of MGMT (PDB entry: 1QNT). The inhibitor molecules were docked into the BG binding pocket, and molecular dynamics simulations with explicit water molecules were carried out. Stabilization energies for the interactions of specific regions of the inhibitor and individual amino acid residues were calculated. The alkyl spacer is located in a cleft along helix 6 of MGMT. With increasing spacer length there is increasing interaction with several amino acid residues which play an important role in the proposed nucleotide flipping mechanism required for DNA repair.
- Reinhard,Hull,Von der Lieth,Eichhorn,Kliem,Kaina,Wiessler
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p. 4050 - 4061
(2007/10/03)
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