Interactions of Isopenicillin N Synthase with Cyclopropyl-Containing Substrate Analogues Reveal New Mechanistic Insight†,‡

Biochemistry ◽  
2007 ◽  
Vol 46 (16) ◽  
pp. 4755-4762 ◽  
Author(s):  
Annaleise R. Howard-Jones ◽  
Jonathan M. Elkins ◽  
Ian J. Clifton ◽  
Peter L. Roach ◽  
Robert M. Adlington ◽  
...  
Keyword(s):  
Substrate Analogues ◽  
Mechanistic Insight ◽  
Isopenicillin N

Structural Studies on the Reaction of Isopenicillin N Synthase with the Truncated Substrate Analogues δ-(l-α-aminoadipoyl)-l-cysteinyl-glycine and δ-(l-α-aminoadipoyl)-l-cysteinyl-d-alanine†,‡

Biochemistry ◽  
2005 ◽  
Vol 44 (17) ◽  
pp. 6619-6628 ◽  
Author(s):  
Alexandra J. Long ◽  
Ian J. Clifton ◽  
Peter L. Roach ◽  
Jack E. Baldwin ◽  
Peter J. Rutledge ◽  
...  
Keyword(s):  
Structural Studies ◽  
Substrate Analogues ◽  
Isopenicillin N

The Interaction of Isopenicillin N Synthase with Homologated Substrate Analogues δ-(L-α-Aminoadipoyl)-L-homocysteinyl-D-Xaa Characterised by Protein Crystallography

ChemBioChem ◽  
2013 ◽  
Vol 14 (5) ◽  
pp. 599-606 ◽  
Author(s):  
Adam Daruzzaman ◽  
Ian J. Clifton ◽  
Robert M. Adlington ◽  
Jack E. Baldwin ◽  
Peter J. Rutledge
Keyword(s):  
Protein Crystallography ◽  
Substrate Analogues ◽  
Isopenicillin N

Arylation of enelactams using TIPSOTf: reaction scope and mechanistic insight

2021 ◽  
Author(s):  
Tomasz J. Idzik ◽  
Zofia M. Myk ◽  
Łukasz Struk ◽  
Magdalena Perużyńska ◽  
Gabriela Maciejewska ◽  
...  
Keyword(s):  
Reaction Mechanism ◽  
Multinuclear Nmr ◽  
Mechanistic Insight ◽  
Nmr Study ◽  
Wide Range

Triisopropylsilyltrifluoromethanesulfonate can be effectively used for the arylation of a wide range of enelactams. The multinuclear NMR study provided deep insights into the reaction mechanism.

New Mechanistic Insight on the PIM-1 Kinase Inhibitor AZD1208 Using Multidrug Resistant Human Erythroleukemia Cell Lines and Molecular Docking Simulations

2019 ◽  
Vol 19 (11) ◽  
pp. 914-926 ◽  
Author(s):  
Maiara Bernardes Marques ◽  
Michael González-Durruthy ◽  
Bruna Félix da Silva Nornberg ◽  
Bruno Rodrigues Oliveira ◽  
Daniela Volcan Almeida ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Site ◽  
Cell Lines ◽  
Chemotherapeutic Agents ◽  
Atp Binding ◽  
Human Leukemia ◽  
Atp Binding Site ◽  
Mechanistic Insight ◽  
Multiple Drugs

Background:PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation, and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype.Objective:In the present work, we tested a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR).Materials and Methods:In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena (resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line, by MTT analyses. The activity of Pgp was ascertained by measuring accumulation and the directional flux of Rh123. Furthermore, we performed a molecular docking simulation to delve into the molecular mechanism of PIM-1 alone, and combined with chemotherapeutic agents (VCR and DNR).Results:Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Docking analysis showed that AZD1208 is capable of performing hydrophobic interactions with PIM-1 ATP- binding-site residues with stronger interaction-based negative free energy (FEB, kcal/mol) than the ATP itself, mimicking an ATP-competitive inhibitory pattern of interaction. On the same way, VCR and DNR may theoretically interact at the same biophysical environment of AZD1208 and also compete with ATP by the PIM-1 active site. These evidences suggest that AZD1208 may induce pharmacodynamic interaction with VCR and DNR, weakening its cytotoxic potential in the ATP-binding site from PIM-1 observed in the in vitro experiments.Conclusion:Finally, the current results could have a pre-clinical relevance potential in the rational polypharmacology strategies to prevent multiple-drugs resistance in human leukemia cancer therapy.

scholarly journals Mechanistic insight into B(C6F5)3 catalyzed imine reduction with PhSiH3 under stoichiometric water conditions

RSC Advances ◽  
2021 ◽  
Vol 11 (34) ◽  
pp. 20961-20969
Author(s):  
Yunqing He ◽  
Wanli Nie ◽  
Ying Xue ◽  
Qishan Hu
Keyword(s):  
Mechanistic Insight ◽  
Excess Water ◽  
Water Conditions ◽  
Imine Reduction ◽  
Water Amount ◽  
Insight Into

Hydrosilylation or amination products? It depends on water amount and nucleophiles like excess water or produced/added amines.

scholarly journals Mechanistic insight into the fluorescence activity of forensic fingerprinting reagents

2021 ◽  
Vol 154 (12) ◽  
pp. 124313
Author(s):  
L. M. Hunnisett ◽  
P. F. Kelly ◽  
S. Bleay ◽  
F. Plasser ◽  
R. King ◽  
...  
Keyword(s):  
Mechanistic Insight ◽  
Insight Into
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