Tag: M.W=350-400

Cheung, Leanna published the artcileIdentification of new MRP4 inhibitors from a library of FDA approved drugs using a high-throughput bioluminescence screen, Recommanded Product: (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone, the publication is Biochemical Pharmacology (Amsterdam, Netherlands) (2015), 93(3), 380-388, database is CAplus and MEDLINE.

Multidrug resistance protein 4 (MRP4) effluxes a wide variety of drugs and endogenous signaling mols. from cells and was proposed as an attractive therapeutic target in several solid tumors, including neuroblastoma and colorectal cancer. MRP4 also regulates the pharmacokinetics of its drug substrates and its absence can increase their tissue penetration. We observed that MRP4 can efflux the bioluminescence substrate D-luciferin, and exploited this phenomenon to develop a robust, high throughput, live cell-based bioluminescent screen to identify new MRP4 inhibitors. We applied this screen to a combined library of 3600 compounds, all of which were either FDA-approved drugs or bioactive compounds with defined mechanisms of action. From the primary screen, 36 compounds effectively inhibited MRP4 (>4-fold increase in bioluminescence), with inhibitors of receptor tyrosine kinases and phosphodiesterases highly over-represented. Selected compounds were tested for their ability to sensitize MRP4-overexpressing cell lines to the MRP4 substrate drugs 6-mercaptopurine and SN-38, with sensitization up to 6.5-fold with the ryanodine receptor antagonist dantrolene. These newly identified MRP4 inhibitors are readily available and are either established drugs or well-characterized bioactive compounds As such, they should be immediately useful as investigative tools, and suitable for testing both in vitro and in vivo.

Biochemical Pharmacology (Amsterdam, Netherlands) published new progress about 115687-05-3. 115687-05-3 belongs to piperazines, auxiliary class Epigenetics,Sirtuin, name is (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone, and the molecular formula is C20H17ClN4O3, Recommanded Product: (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Devine, William published the artcileProtozoan parasite growth inhibitors discovered by cross-screening yield potent scaffolds for lead discovery, Formula: C17H27BN2O4S, the publication is Journal of Medicinal Chemistry (2015), 58(14), 5522-5537, database is CAplus and MEDLINE.

Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), the authors have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, the authors describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors’ biol. activities against these parasites. In doing this, the authors have identified several potent proliferation inhibitors for each pathogen, such as NEU-924, I, for T. cruzi and NEU-1017, II, for L. major and P. falciparum.

Journal of Medicinal Chemistry published new progress about 914610-39-2. 914610-39-2 belongs to piperazines, auxiliary class Piperazine,Boronic acid and ester,Sulfamide,Benzene,Piperazine,Boronate Esters,Boronic acid and ester,, name is 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine, and the molecular formula is C17H27BN2O4S, Formula: C17H27BN2O4S.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Gobbo, Dorothea published the artcileInvestigating Drug-Target Residence Time in Kinases through Enhanced Sampling Simulations, Recommanded Product: 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine, the publication is Journal of Chemical Theory and Computation (2019), 15(8), 4646-4659, database is CAplus and MEDLINE.

It is widely accepted that drug-target association and dissociation rates directly affect drug efficacy and safety. To rationally optimize drug binding kinetics, one must know the at. arrangement of the protein-ligand complex during the binding/unbinding process in order to detect stable and metastable states. Whereas exptl. approaches can determine kinetic constants with fairly good accuracy, computational approaches based on mol. dynamics (MD) simulations can deliver the atomistic details of the unbinding process. Furthermore, they can also be utilized prospectively to predict residence time (i.e., the inverse of unbinding kinetics constant, k_off) with an acceptable level of accuracy. Here, we report a novel method based on adiabatic bias MD with an electrostatics-like collective variable (dubbed elABMD) for sampling protein-ligand dissociation events in two kinases. elABMD correctly ranked a ligand series on glucokinase, in agreement with exptl. data and previous calculations Subsequently, we applied the new method prospectively to a congeneric series of GSK-3β inhibitors. For this series, new crystal structures were generated and the residence time was exptl. measured with surface plasmon resonance (SPR). There was good agreement between computational predictions and exptl. measures, suggesting that elABMD is an innovative and efficient tool for calculating residence times.

Journal of Chemical Theory and Computation published new progress about 914610-39-2. 914610-39-2 belongs to piperazines, auxiliary class Piperazine,Boronic acid and ester,Sulfamide,Benzene,Piperazine,Boronate Esters,Boronic acid and ester,, name is 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine, and the molecular formula is C17H27BN2O4S, Recommanded Product: 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Bodner, Ruth A. published the artcilePharmacological promotion of inclusion formation: a therapeutic approach for Huntington’s and Parkinson’s diseases, Recommanded Product: (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone, the publication is Proceedings of the National Academy of Sciences of the United States of America (2006), 103(11), 4246-4251, database is CAplus and MEDLINE.

Misfolded proteins accumulate in many neurodegenerative diseases, including huntingtin in Huntington’s disease and α-synuclein in Parkinson’s disease. The disease-causing proteins can take various conformations and are prone to aggregate and form larger cytoplasmic or nuclear inclusions. One approach to the development of therapeutic intervention for these diseases has been to identify chem. compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington’s disease and Parkinson’s disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces α-synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathol. in both Huntington’s and Parkinson’s diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding.

Proceedings of the National Academy of Sciences of the United States of America published new progress about 115687-05-3. 115687-05-3 belongs to piperazines, auxiliary class Epigenetics,Sirtuin, name is (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone, and the molecular formula is C20H17ClN4O3, Recommanded Product: (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Palazzolo, Isabella published the artcileB2 attenuates polyglutamine-expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy, Name: (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone, the publication is Journal of Neuroscience Research (2010), 88(10), 2207-2216, database is CAplus and MEDLINE.

Expanded polyglutamine tracts cause neurodegeneration through a toxic gain-of-function mechanism. Generation of inclusions is a common feature of polyglutamine diseases and other protein misfolding disorders. Inclusion formation is likely to be a defensive response of the cell to the presence of unfolded protein. Recently, the compound B2 has been shown to increase inclusion formation and decrease toxicity of polyglutamine-expanded huntingtin in cultured cells. We explored the effect of B2 on spinal and bulbar muscular atrophy (SBMA). SBMA is caused by expansion of polyglutamine in the androgen receptor (AR) and is characterized by the loss of motor neurons in the brainstem and spinal cord. We found that B2 increases the deposition of mutant AR into nuclear inclusions, without altering the ligand-induced aggregation, expression, or subcellular distribution of the mutant protein. The effect of B2 on inclusions was associated with a decrease in AR transactivation function. We show that B2 reduces mutant AR toxicity in cell and fly models of SBMA, further supporting the idea that accumulation of polyglutamine-expanded protein into inclusions is protective. Our findings suggest B2 as a novel approach to therapy for SBMA. © 2010 Wiley-Liss, Inc.

Journal of Neuroscience Research published new progress about 115687-05-3. 115687-05-3 belongs to piperazines, auxiliary class Epigenetics,Sirtuin, name is (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone, and the molecular formula is C20H17ClN4O3, Name: (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Wilson, Daniel J. published the artcileA continuous fluorescence displacement assay for BioA: An enzyme involved in biotin biosynthesis, Product Details of C20H17ClN4O3, the publication is Analytical Biochemistry (2011), 416(1), 27-38, database is CAplus and MEDLINE.

Cofactor biosynthetic pathways represent a rich source of potential antibiotic targets. The second step in biotin biosynthesis is performed by BioA, a pyridoxal 5′-phosphate (PLP)-dependent enzyme. This enzyme has been confirmed as a candidate target in Mycobacterium tuberculosis; however, the current bioassay used to measure BioA activity is cumbersome and low throughput. Here we describe the design, development, and optimization of a continuous coupled fluorescence displacement assay to measure BioA activity. In this coupled assay, BioD converts the product of the BioA-catalyzed reaction into dethiobiotin, which is subsequently detected by displacement of a fluorescently labeled dethiobiotin probe from streptavidin. The assay was further adapted to a high-throughput screening format and validated against the LOPAC¹²⁸⁰ library.

Analytical Biochemistry published new progress about 115687-05-3. 115687-05-3 belongs to piperazines, auxiliary class Epigenetics,Sirtuin, name is (4-Chlorophenyl)(4-(8-nitroquinolin-5-yl)piperazin-1-yl)methanone, and the molecular formula is C6H8N2, Product Details of C20H17ClN4O3.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics

Bachovchin, Kelly A. published the artcileImprovement of aqueous solubility of lapatinib-derived analogues: identification of a quinolinimine lead for human African trypanosomiasis drug development, Synthetic Route of 914610-39-2, the publication is Journal of Medicinal Chemistry (2019), 62(2), 665-687, database is CAplus and MEDLINE.

Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in I, which was part of a series typically associated with poor aqueous solubility In this report, we present various medicinal chem. strategies that were used to increase the aqueous solubility and improve the physicochem. profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC₅₀)) was established, as part of the lead selection process. Increasing the sp³ carbon content of I resulted in II (0.19 μM EC₅₀ against T. brucei and 990 μM aqueous solubility). Further chem. exploration of II yielded III, a trypanocidal quinolinimine (EC₅₀: 0.013 μM; aqueous solubility: 880 μM; and CEC₅₀: 0.18 μM). Compound III reduced parasitemia 10⁹ fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.

Journal of Medicinal Chemistry published new progress about 914610-39-2. 914610-39-2 belongs to piperazines, auxiliary class Piperazine,Boronic acid and ester,Sulfamide,Benzene,Piperazine,Boronate Esters,Boronic acid and ester,, name is 1-Methyl-4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine, and the molecular formula is C17H27BN2O4S, Synthetic Route of 914610-39-2.

Referemce:
https://en.wikipedia.org/wiki/Piperazine,
Piperazines – an overview | ScienceDirect Topics