42923-77-3Relevant articles and documents
Inhibition of Complex I by Isoquinoline Derivatives Structurally Related to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)
Mcnaught, Kevin St. P.,Thull, Ulrike,Carrupt, Pierre-Alain,Altomare, Cosimo,Cellamare, Saverio,Carotti, Angelo,Testa, Bernard,Jenner, Peter,Marsden, C. David
, p. 1903 - 1912 (1995)
Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 ca. 22 mM). At 10 mM, only isoquinoline (23.1 percent), 6,7-dimethoxyisoquinoline (89.6 percent), and N-methylsalsolinol (34.8 percent) inhibited (P +, so respiratory inhibition may underlie their reported neurotoxicity.
Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds
Vara, Brandon A.,Levi, Samuel M.,Achab, Abdelghani,Candito, David A.,Fradera, Xavier,Lesburg, Charles A.,Kawamura, Shuhei,Lacey, Brian M.,Lim, Jongwon,Methot, Joey L.,Xu, Zangwei,Xu, Haiyan,Smith, Dustin M.,Piesvaux, Jennifer A.,Miller, J. Richard,Bittinger, Mark,Ranganath, Sheila H.,Bennett, David J.,Dimauro, Erin F.,Pasternak, Alexander
, p. 653 - 661 (2021/04/12)
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition in vivo, supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising in vitro profiles.
Easy Access to 2,4-Disubstituted Cyclopentenones by a Gold(III)-Catalyzed A3-Coupling/Cyclization Cascade
Hu, Xiwen,Li, Jian,Liu, Li,Xu, Yue,Zhu, Shangrong
supporting information, p. 9478 - 9483 (2020/12/21)
An efficient and convenient synthesis of 2,4-disubstituted cyclopentenones has been achieved through a Au(III)-catalyzed isomerization-A3-coupling/cyclization cascade. A possible mechanism involving an initial Au(III)-catalyzed isomerization, A3-type coupling, and cyclization via an enol intermediate is postulated.
Synthesis and evaluation of tetrahydroisoquinoline-benzimidazole hybrids as multifunctional agents for the treatment of Alzheimer's disease
Fang, Yuying,Zhou, Huihao,Gu, Qiong,Xu, Jun
, p. 133 - 145 (2019/02/17)
A novel series of tetrahydroisoquinoline-benzimidazole hybrids have been designed and synthesized as multifunctional agents against Alzheimer's disease (AD). These compounds were evaluated for their inhibition of neuroinflammation and human β-secretase (hBACE1), and neuroprotective activity. Among them, compound BD3 possessed significant anti-neuroinflammatory activity (IC50 = 5.07 μM against nitric oxide production) through inhibiting the expression and secretion of proinflammatory cytokines in BV2 cells. Compound BD3 also exhibited moderate hBACE1 inhibitory activity (65.7% inhibition at 20 μM) and potent neuroprotective effect by increasing GSH level and reducing ROS production (91.8% cell viability at 5 μM). Parallel artificial membrane permeation assay demonstrated that BD3 could cross the blood-brain barrier (BBB). Thus, this study demonstrates that the compounds with tetrahydroisoquinoline-benzimidazole scaffold are potential anti-AD agents, and they are worth for the further development.
