scholarly journals Characterization of platinum(II) complexes exhibiting inhibitory activity against the 20S proteasome

2020 ◽  
Vol 7 (8) ◽  
pp. 200545
Author(s):  
Tatsuto Kiwada ◽  
Hiromu Katakasu ◽  
Serina Okumura ◽  
Akira Odani
Keyword(s):  
Inhibitory Activity ◽  
Chemical Structure ◽  
Competitive Inhibition ◽  
Proteasome Inhibitors ◽  
Platinum Complex ◽  
Platinum Complexes ◽  
Binding Mode ◽  
Structure Activity Relationships ◽  
Structure Activity

Proteasome inhibitors are useful for biochemical research and clinical treatment. In our previous study, we reported that the 4N-coordinated platinum complexes with anthracenyl ring and heterocycle exhibited proteasome-inhibitory activity. In the present study, the structure–activity relationships and characterization of these complexes were determined for the elucidation of the role of aromatic ligands. Lineweaver–Burk analysis revealed that the chemical structure of heterocycles affects the binding mode of platinum complexes. Platinum complexes with anthracenyl ring and pyridine showed competitive inhibition, although platinum complexes with anthracenyl ring and phenanthroline showed non-competitive inhibition. The structure–activity relationships demonstrated that anthracenyl moiety plays a crucial role in proteasome-inhibitory activity. The platinum complexes with naphthyl or phenyl rings exhibited lower inhibitory activities than the platinum complex with anthracenyl ring. The reactivity with N-acetylcysteine varied according to the chemical structure of complexes.

scholarly journals Identification of the first surrogate agonists for the G protein-coupled receptor GPR132

RSC Advances ◽  
2015 ◽  
Vol 5 (60) ◽  
pp. 48551-48557 ◽  
Author(s):  
Mohamed A. Shehata ◽  
Hanna Belcik Christensen ◽  
Vignir Isberg ◽  
Daniel Sejer Pedersen ◽  
Andreas Bender ◽  
...  
Keyword(s):  
G Protein ◽  
Binding Mode ◽  
Orphan Receptor ◽  
G Protein Coupled Receptor ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
G Protein Coupled

We report the first pharmacological tool agonist for in vitro characterization of the orphan receptor GPR132, preliminary structure–activity relationships based on 32 analogs and a suggested binding mode from docking.

scholarly journals Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jerónimo Laiolo ◽  
Priscila Ailin Lanza ◽  
Oscar Parravicini ◽  
Cecilia Barbieri ◽  
Daniel Insuasty ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Molecular Complexes ◽  
Binding Mode ◽  
Reversal Agents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Doxorubicin Toxicity ◽  
Key Residues ◽  
Nanomolar Range ◽  
Experimental Structure

AbstractP-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

ChemInform Abstract: Structure-Activity Relationships of Biflavonoids for β-Secretase (BACE-1) Inhibitory Activity.

ChemInform ◽  
2013 ◽  
Vol 44 (11) ◽  
pp. no-no
Author(s):  
Hiroaki Sasaki ◽  
Yuki Kitoh ◽  
Kazuhiko Miki ◽  
Kaoru Kinoshita ◽  
Kiyotaka Koyama ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Abstract Structure ◽  
Bace 1

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

2021 ◽  
Author(s):  
Jerónimo Laiolo ◽  
Priscila Ailin Lanza ◽  
Oscar Parravicini ◽  
Cecilia Barbieri ◽  
Daniel Insuasty ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Molecular Complexes ◽  
Binding Mode ◽  
Reversal Agents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Doxorubicin Toxicity ◽  
Key Residues ◽  
Nanomolar Range ◽  
Experimental Structure

Abstract P-gp-associated multidrug resistance (MDR) is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone moiety favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

Structure-activity relationships in the Hill inhibitory activity of substituted phenylureas

1987 ◽  
Vol 35 (4) ◽  
pp. 479-483 ◽  
Author(s):  
Patrick Camilleri ◽  
John R. Bowyer ◽  
Terence Gilkerson ◽  
Barbara Odell ◽  
Roger C. Weaver
Keyword(s):  
Inhibitory Activity ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
The Hill

scholarly journals Ubiquitin-Proteasome Modulating Dolabellanes and Secosteroids from Soft Coral Clavularia flava

Marine Drugs ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 39
Author(s):  
Che-Yen Chiu ◽  
Xue-Hua Ling ◽  
Shang-Kwei Wang ◽  
Chang-Yih Duh
Keyword(s):  
Inhibitory Activity ◽  
Structure Elucidation ◽  
Chemical Structure ◽  
Soft Coral ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Structural Elucidation ◽  
Bioactive Molecules ◽  
High Content Screening ◽  
Ubiquitin Proteasome

We performed a high-content screening (HCS) assay aiming to discover bioactive molecules with proteasome inhibitory activity. By structural elucidation, we identified six compounds purified from soft coral Clavularia flava, which potentiates proteasome inhibition. Chemical structure elucidation revealed they are dolabellane- and secosteroid-based compounds including a new dolabellane, clavinflol C (1), three known dolabellanes, stolonidiol (2), stolonidiol-17-acetate (3), and clavinflol B (4) as well as two new secosteroids, 3β,11-dihydroxy-24-methyl-9,11-secocholest-5-en-9,23-dione (5) and 3β,11-dihydroxy-24-methylene-9,11-secocholest-5-en-9,23-dione (6). All six compounds show less cytotoxicity than those of known proteasome inhibitors, bortezomib and MG132. In summary, the high-content measurements of control inhibitors, bortezomib and MG132, manifest the highest ratio >2 in high-content measurement. Of the isolated compounds, 2 and 5 showed higher activity, followed by 3 and 6, and then 1 and 4 exhibited moderate inhibition.

scholarly journals UFLC-MS-IT-TOF and Bioassay Guided Isolation of Flavonoids as Xanthine Oxidase Inhibitors from Diospyros dumetorum

2017 ◽  
Vol 12 (11) ◽  
pp. 1934578X1701201
Author(s):  
Zhen-Tao Deng ◽  
Tong-Hua Yang ◽  
Xiao-Yan Huang ◽  
Xing-Long Chen ◽  
Jian-Gang Zhang ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Inhibitory Activity ◽  
Folk Medicine ◽  
Hydroxyl Groups ◽  
Active Constituents ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Pulmonary Abscess ◽  
Xanthine Oxidase Inhibitors

Diospyros dumetorum is an important folk medicine for treating pulmonary abscess and inflammation. The leaves of D. dumetorum revealed xanthine oxidase (XOD) inhibitory activity. With the guidance of UFLC-MS-IT-TOF analyses combined with bioassay in vitro, 15 flavonoids were isolated from the active parts of D. dumetorum. Except for 11 (IC50 > 200μM), all compounds showed obvious XOD inhibitory activity with IC50 values of 32.5 ± 0.7 ~ 145.0 ± 3.3 μM. The preliminary structure-activity relationships study suggested that glycosylation on C-3 was unfavorable for XOD inhibitory activity; hydroxyl groups on ring B were essential for maintaining activity; the activity was closely related with the position of galloylation. This is the first recognition of the XOD inhibitory activity and active constituents of D. dumetorum, and will provide valuable information for this plant as a new resource for treating hyperuricemia and gout.

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