- Deglycase-activity oriented screening to identify DJ-1 inhibitors
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The oncoprotein and Parkinson's disease-associated enzyme DJ-1/PARK7 has emerged as a promiscuous deglycase that can remove methylglyoxal-induced glycation adducts from both proteins and nucleotides. However, dissecting its structural and enzymatic functions remains a challenge due to the lack of potent, specific, and pharmacokinetically stable inhibitors targeting its catalytic site (including Cys106). To evaluate potential drug-like leads against DJ-1, we leveraged its deglycase activity in an enzyme-coupled, fluorescence lactate-detection assay based on the recent understanding of its deglycation mechanism. In addition, we developed assays to directly evaluate DJ-1's esterase activity using both colorimetric and fluorescent substrates. The resulting optimized assay was used to evaluate a library of potential reversible and irreversible DJ-1 inhibitors. The deglycase activity-oriented screening strategy described herein establishes a new platform for the discovery of potential anti-cancer drugs.
- David, Yael,Finkin-Groner, Efrat,Fukase, Yoshiyuki,Huggins, David J.,Maksimovic, Igor,Michino, Mayako,Myers, Robert W.,Sun, Shan,Zheng, Qingfei
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supporting information
p. 1232 - 1238
(2021/09/28)
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- Discovery of membrane active benzimidazole quinolones-based topoisomerase inhibitors as potential DNA-binding antimicrobial agents
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A series of novel benzimidazole quinolones as potential antimicrobial agents were designed and synthesized. Most of the prepared compounds exhibited good or even stronger antimicrobial activities in comparison with reference drugs. The most potent compound 15m was membrane active and did not trigger the development of resistance in bacteria. It not only inhibited the formation of biofilms but also disrupted the established Staphylococcus aureus and Escherichia coli biofilms. It was able to inhibit the relaxation activity of E. coli topoisomerase IV at 10 μM concentration. Moreover, this compound also showed low toxicity against mammalian cells. Molecular modeling and experimental investigation of compound 15m with DNA suggested that this compound could effectively bind with DNA to form a steady 15m-DNA complex which might further block DNA replication to exert the powerful bioactivities.
- Zhang, Ling,Addla, Dinesh,Ponmani, Jeyakkumar,Wang, Ao,Xie, Dan,Wang, Ya-Nan,Zhang, Shao-Lin,Geng, Rong-Xia,Cai, Gui-Xin,Zhou, Cheng-He,Li, Shuo
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p. 160 - 182
(2018/05/17)
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- SMALL MOLECULE INDUCERS OF GDNF AS POTENTIAL NEW THERAPEUTICS FOR NEUROPSYCHIATRIC DISORDERS
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The invention provides a compound having the structure (I), wherein A is a substituted or unsubstituted ring; Z is present or absent and when present is (II), wherein n is 0, 1, 2, 3, or 4; Y is -(CR11R12)-, -NH(CR11R12)- or -O(CR11R12)- wherein R11 and R12 are each hydrogen or combine to form a carbonyl; and wherein R1 to R10 are herein as described.
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Page/Page column 101; 102
(2013/03/26)
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- Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication
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The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure-activity relationship (SAR) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N′-((1H-benzo[d]imidazol-2-yl)methyl)- N′-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC50 value of 13 nM in a CXCR4 125I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC50 of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 μM. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.
- Skerlj, Renato T.,Bridger, Gary J.,Kaller, Al,McEachern, Ernest J.,Crawford, Jason B.,Zhou, Yuanxi,Atsma, Bem,Langille, Jonathon,Nan, Susan,Veale, Duane,Wilson, Trevor,Harwig, Curtis,Hatse, Sigrid,Princen, Katrien,De Clercq, Erik,Schols, Dominique
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supporting information; experimental part
p. 3376 - 3388
(2010/09/05)
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- Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction
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A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D 4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin- 1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 μmol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D 4 selective agonism in this series of analogues.
- Cowart, Marlon,Latshaw, Steven P.,Bhatia, Pramila,Daanen, Jerome F.,Rohde, Jeffrey,Nelson, Sherry L.,Patel, Meena,Kolasa, Teodozyi,Nakane, Masaki,Uchic, Marie E.,Miller, Loan N.,Terranova, Marc A.,Chang, Renjie,Donnelly-Roberts, Diana L.,Namovic, Marian T.,Hollingsworth, Peter R.,Martino, Brenda R.,Lynch III, James J.,Sullivan, James P.,Hsieh, Gin C.,Moreland, Robert B.,Brioni, Jorge D.,Stewart, Andrew O.
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p. 3853 - 3864
(2007/10/03)
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- Blue Copper Models. Spectroscopic and Electrochemical Studies of Copper(II) Complexes with New Ligand Systems containing Sulphur and Nitrogen Donor Atoms
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A series of new polyfunctional ligands derived from the condensation of 1-isopropyl- or 1-phenyl-3-formyl-2(1H)-pyridinethione with aminoalkylthioalkylbenzimidazoles having alkyl chains of various lengths between the donor atoms and the corresponding copper(II) complexes have been synthesized and spectroscopically characterized.The complexes show marked structural variations according to the length of the alkyl chains of the ligands, square planar, square pyramidal, trigonal bipyramidal, and distorted five-co-ordinate, and for one complex a wider range of distorted structures, including four- and five-co-ordinate, is accessible depending on the solvent and physical state.Electrochemistry in non-aqueous solvents indicates that the copper(II) complexes undergo a quasi-reversible one-electron reduction at markedly positive potentials, in the range from +0.23 to 0.35 V vs. saturated calomel electrode.The complete chemical reversibility of the Cu(II)-Cu(I) redox change has been tested by controlled-potential electrolysis.The five-co-ordinate complexes exhibit reduction potentials 0.1 V higher than the square-planar complexes, independently of their actual geometry, square pyramidal, trigonal bipyramidal, or intermediate between these.
- Casella, Luigi,Gullotti, Michele,Pintar, Alessandro,Pinciroli, Piorella,Vigano, Roberto,Zanello, Piero
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p. 1161 - 1170
(2007/10/02)
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