13602-12-5Relevant articles and documents
Design, synthesis, and biological evaluation of 17-cyclopropylmethyl-3, 14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido] morphinan derivatives as peripheral selective μ opioid receptor agents
Yuan, Yunyun,Elbegdorj, Orgil,Chen, Jianyang,Akubathini, Shashidhar K.,Zhang, Feng,Stevens, David L.,Beletskaya, Irina O.,Scoggins, Krista L.,Zhang, Zhenxian,Gerk, Phillip M.,Selley, Dana E.,Akbarali, Hamid I.,Dewey, William L.,Zhang, Yan
, p. 10118 - 10129 (2012)
Peripheral selective μ opioid receptor (MOR) antagonists could alleviate the symptoms of opioid-induced constipation (OIC) without compromising the analgesic effect of opioids. However, a variety of adverse effects were associated with them, partially due to their relatively low MOR selectivity. NAP, a 6β-N-4′-pyridyl substituted naltrexamine derivative, was identified previously as a potent and highly selective MOR antagonist mainly acting within the peripheral nervous system. The noticeable diarrhea associated with it prompted the design and synthesis of its analogues in order to study its structure-activity relationship. Among them, compound 8 showed improved pharmacological profiles compared to the original lead, acting mainly at peripheral while increasing the intestinal motility in morphine-pelleted mice (ED50 = 0.03 mg/kg). The slight decrease of the ED50 compared to the original lead was well compensated by the unobserved adverse effect. Hence, this compound seems to be a more promising lead to develop novel therapeutic agents toward OIC.
Ligand-regulated assemblies of three 1D to 3D Cu(II) coordination polymers: Structural diversities and magnetic properties
Cuo, Lei-Lei,Kang, Yi-Fan,Ma, Yang-Min,Wang, Yun-Luo,Xu, Li,Zhang, Wen-Qian
, (2020)
Three structurally diverse Cu(II) coordination polymers (CPs) from one-dimension (1D) to three-dimension (3D) upon nicotinate N-oxide (NNO) and isonicotinate N-oxide (INO) ligands have been synthesized solvothermally. CP 1 [Cu3(NNO)4(OH)2(H2O)2]n based on NNO ligand displays a 1D wavy double-chain. CP 2 [Cu(INO)(OH)]n based on INO ligand possesses a 2D wavy double-sheet. CP 3 [Cu(INO)(CH3O)]n based on INO ligand exhibits a 3D framework with 1D wavy channels. Structural comparisons indicate that the position of functional group of ligand, the coordination modes of ligand, the solvent system determine these diversified CPs. And Moreover, the structural diversity of CPs 1–3 further result in their different magnetic behaviors.
Design of 3-D europium(iii)-organic frameworks based on pyridine carboxylate N-oxide and acyclic binary carboxylate: Syntheses, structures, and luminescence properties
Zhang, Lijuan,Xu, Donghua,Zhou, Yunshan,Jiang, Fei
, p. 2470 - 2478 (2010)
Four europium(iii) complexes of 3-D open frameworks [Eu2(NNO) 4(ox)(H2O)2]n (1), [Eu 2(INO)2(ox)2(H2O)2] n (2), {[Eu2(INO)2(suc)2]·2. 99H2O}n (3) and {[Eu2(suc)3(H 2O)2]·H2O}n (4) (HNNO = nicotinic acid N-oxide, H2ox = oxalic acid, HINO = isonicotinic acid, H2suc = succinic acid) have been synthesized and characterized by IR, elemental analysis, TG/DTA and single-crystal X-ray diffraction analysis. Each of the four complexes has 1-D channels, and in 3 and 4 these are filled with solvent water molecules, making them bigger than in 1 and 2, where no lattice water molecules can reside. The formation of the four 3-D europium(iii) frameworks of different molecular and crystal structures reflects the influence of the ligands' coordination modes, the length of the acyclic binary carboxylates, the ligand conformation as well as the molar ratio of reactants. At room temperature, all the complexes in the solid state exhibit typical red luminescence from Eu3+ ions, indicating effective energy transfer from the ligand to Eu3+ ion; however, their luminescence intensities are clearly different. The luminescence of 3 is the most intense due to the absence of coordinated water, while the complexes 1, 2 and 4 exhibit weaker luminescence due to oscillation of coordinated water molecules, which partially quenches their luminescence.
Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and in Vivo Studies
Jung, Sascha,Fuchs, Natalie,Johe, Patrick,Wagner, Annika,Diehl, Erika,Yuliani, Tri,Zimmer, Collin,Barthels, Fabian,Zimmermann, Robert A.,Klein, Philipp,Waigel, Waldemar,Meyr, Jessica,Opatz, Till,Tenzer, Stefan,Distler, Ute,R?der, Hans-Joachim,Kersten, Christian,Engels, Bernd,Hellmich, Ute A.,Klein, Jochen,Schirmeister, Tanja
, p. 12322 - 12358 (2021/09/02)
Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorable metabolism and biodistribution by accumulation in mice brain tissue after intraperitoneal and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2 (2e/4e) with nanomolar EC50 values (0.14/0.80 μM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations.
