6301-83-3Relevant academic research and scientific papers
Triazolopyrimidines identified as reversible myeloperoxidase inhibitors
Duclos, Franck,Abell, Lynn M.,Harden, David G.,Pike, Kristen,Nowak, Kimberly,Locke, Gregory A.,Duke, Gerald J.,Liu, Xiaoqin,Fernando, Gayani,Shaw, Scott A.,Vokits, Benjamin P.,Wurtz, Nicholas R.,Viet, Andrew,Valente, Meriah N.,Stachura, Sylwia,Sleph, Paul,Khan, Javed A.,Gao, Ji,Dongre, Ashok R.,Zhao, Lei,Wexler, Ruth R.,Gordon, David A.,Kick, Ellen K.
, p. 2093 - 2099 (2017/11/22)
Myeloperoxidase, a mammalian peroxidase involved in the immune system as an anti-microbial first responder, can produce hypochlorous acid in response to invading pathogens. Myeloperoxidase has been implicated in several chronic pathological diseases due to the chronic production of hypochlorous acid, as well as other reactive radical species. A high throughput screen and triaging protocol was developed to identify a reversible inhibitor of myeloperoxidase toward the potential treatment of chronic diseases such as atherosclerosis. The identification and characterization of a reversible myeloperoxidase inhibitor, 7-(benzyloxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine is described.
Monosaccharide-linked inhibitors of O6-methylguanine-DNA methyltransferase (MGMT): Synthesis, molecular modeling, and structure-activity relationships
Reinhard,Hull,Von der Lieth,Eichhorn,Kliem,Kaina,Wiessler
, p. 4050 - 4061 (2007/10/03)
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.
8-substituted O6-benzylguanine, substituted 6(4)-(benzyloxy)pyrimidine, and related derivatives as inactivators of human O6-alkylguanine-DNA alkyltransferase
Chae,Swenn,Kanugula,Dolan,Pegg,Moschel
, p. 359 - 365 (2007/10/02)
Several 8-substituted O6-benzylguanines, 2- and/or 8-substituted 6- (benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6- (benzyloxy)-s-triazine were tested for their ability to inactivate the human DNA repair protein, O6/
