scholarly journals Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 935 ◽  
Author(s):  
Valeria Cavalloro ◽  
Katia Russo ◽  
Francesca Vasile ◽  
Luca Pignataro ◽  
Archimede Torretta ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Catalytic Domain ◽  
Memory Loss ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Chiral Resolution ◽  
Regulatory Domains ◽  
Downstream Effectors ◽  
Configuration Assignment ◽  
Ic50 Values

Alzheimer’s disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains.

scholarly journals Chiral Resolution of a New Agent against Memory Impairment Connected to Neurodegenerative Diseases

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 15
Author(s):  
Cavalloro ◽  
Rui ◽  
Rossino ◽  
Rossi ◽  
Rapetti ◽  
...  
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Memory Impairment ◽  
Memory Loss ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Chiral Resolution ◽  
Low Levels

Nowadays, the incidence of neurodegenerative diseases is increasing, and these disorders will become one of the main challenges for medicine and public health in future years. Particularly, memory loss characterizes many neurodegenerative pathologies, and it is often related to low levels of cyclic adenosine monophosphate (cAMP). [...]

scholarly journals Chiral Resolution, Absolute Configuration Assignment, and Genotoxicity Evaluation of Racemic 3,4-Dihydroquinazoline as a Novel Anticancer Agent

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Junseong Ahn ◽  
Dohyeong Ko ◽  
Seyoung Yang ◽  
Kwang H. Moon ◽  
Jiwon Woo ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Anticancer Agent ◽  
Metabolic Activation ◽  
Chiral Resolution ◽  
Drug Candidate ◽  
Bacterial Strains ◽  
Configuration Assignment ◽  
Preclinical And Clinical Studies ◽  
Human A549 ◽  
A549 Lung

If a new drug candidate will be a mixture of enantiomers, both enantiomers should be separately studied for at least latent genotoxicity as early as possible since the thalidomide tragedy. Our group has recently reported that KCP-10043F (OZ-001) as a racemate (±)-3,4-dihydroquinazoline derivative strongly represses the proliferation of human A549 lung cancer cells by caspase-mediated apoptosis via STAT3 inactivation. To investigate the possible teratological effects of the two enantiomers of a racemic KCP-10043F, therefore chiral resolution of (±)-KCP-10043F was performed and subsequently followed by a series of chemical processes to afford the corresponding chiral diastereomers. By using 1H NMR anisotropy method, the absolute configuration (+)-KCP-10043F and (−)-KCP-10043F could be assigned as S and R configuration, respectively. The bacterial reverse mutation test (Ames test) for racemate (±)-KCP-10043F and its two enantiomers exhibited that all three stereoisomers were found to be nongenotoxic against five bacterial strains with/without metabolic activation. In addition, (R)-(−)-KCP-10043F displayed almost equal anticancer activity to (S)-(+)-KCP-10043F against three cancer cell lines. Based on these overall results, racemate KCP-10043F (OZ-001) could be used for our ongoing preclinical and clinical studies without the expensive asymmetric process and/or chiral separation.

scholarly journals Novel Enantiopure Sigma Receptor Modulators: Quick (Semi-)Preparative Chiral Resolution via HPLC and Absolute Configuration Assignment

Molecules ◽  
2016 ◽  
Vol 21 (9) ◽  
pp. 1210 ◽  
Author(s):  
Marta Rui ◽  
Annamaria Marra ◽  
Vittorio Pace ◽  
Markus Juza ◽  
Daniela Rossi ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Chiral Resolution ◽  
Sigma Receptor ◽  
Configuration Assignment ◽  
Receptor Modulators

scholarly journals Molecular Mechanism of Light-Induced Acceleration of the Adenosine Triphosphate Conversion to the Cyclic Adenosine Monophosphate Catalyzed by the Photoactivated Adenylyl Cyclase bPAC

2020 ◽  
Author(s):  
Alexander Nemukhin ◽  
Maria Khrenova ◽  
Anna M. Kulakova
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Adenylyl Cyclase ◽  
Adenosine Triphosphate ◽  
Catalytic Domain ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Bluf Domain ◽  
Dynamics Simulations ◽  
Photoactivated Adenylyl Cyclase

<p>We report the first computational characterization of an optogenetic system composed of two photosensing BLUF (<u>b</u>lue <u>l</u>ight sensor <u>u</u>sing <u>f</u>lavin adenine dinucleotide) domains and two catalytic adenylyl cyclase (AC) domains. Conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and pyrophosphate (PPi) catalyzed by ACs coupled with excitation in photosensing domains has emerged in the focus of modern optogenetic applications because of the request in photoregulated enzymes to modulate cellular concentrations of signaling messengers. The photoactivated adenylyl cyclase from the soil bacterium <i>Beggiatoa sp.</i> (bPAC) is an important model showing considerable increase of the ATP to cAMP conversion rate in the catalytic domain after the illumination of the BLUF domain. The 1 μs classical molecular dynamics simulations reveal that the activation of the BLUF domain leading to tautomerization of Gln49 in the chromophore binding pocket results in switching of position of the side chain of Arg278 in the active site of AC. Allosteric signal transmission pathways between Gln49 from BLUF and Arg278 from AC were revealed by the dynamical network analysis. The Gibbs energy profiles of the ATP → cAMP + PPi reaction computed using QM(DFT(ωB97X-D3/6-31G**))/MM(CHARMM) molecular dynamics simulations for both Arg278 conformations in AC clarify the reaction mechanism. In the light-activated system, the corresponding arginine conformation stabilizes the pentacoordinated phosphorus of the α-phosphate group in the transition state, thus lowering the activation energy. Simulations of the bPAC system with the Tyr7Phe replacement in BLUF demonstrate occurrence of both arginine conformations in an equal ratio, explaining the experimentally observed intermediate catalytic activity of the bPAC-Y7F variant as compared with the dark and light states of the wild type bPAC. </p>

scholarly journals Human platelet cGI-PDE: expression in yeast and localization of the catalytic domain by deletion mutagenesis

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1321-1329 ◽  
Author(s):  
PP Cheung ◽  
H Xu ◽  
MM McLaughlin ◽  
FA Ghazaleh ◽  
GP Livi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Blot Analysis ◽  
Catalytic Domain ◽  
Structural Information ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Intracellular Camp

Cyclic adenosine monophosphate (cAMP) is an important modulator of platelet responses to agonists. Cyclic nucleotide phosphodiesterase (PDE) controls intracellular cAMP concentrations by hydrolyzing it to AMP. The major PDE activity in platelets is PDE3A (cyclic guanosine monophosphate [cGMP]-inhibited PDE). To obtain structural information on platelet PDE3A, we cloned the enzyme cDNA from a human erythroleukemia cell (HEL) library since the cell line expresses many platelet proteins. This clone consists of 87% of the full-length human myocardial PDE3A cDNA, spanning from nucleotides 456 to 4606, and is identical in sequence. The nucleotide coding for the N terminal 179 amino acid sequence (nt 1–536) as well as four other cDNAs (nt 1459–1632, nt 1765–1986, nt 2152–2538, and nt 2978–3375) obtained by RT-PCR of platelet RNA are also identical to the myocardial sequences, indicating that the HEL, myocardial, and platelet PDE3As are the same. Northern blot analysis of HEL cell RNA detected two mRNAs of 7.5 and 4.4 kb. Four new deletion mutants are reported. PDE 3A delta 1 and PDE 3A delta 2, encoding amino acids 665 to 1141 and amino acids 679 to 1141, respectively, were expressed in a PDE-deficient yeast. They displayed PDE activities of 172 and 79 pmol/mg/min, respectively. PDE 3A delta 3 and PDE 3A delta 4, encoding amino acids 686 to 1141 and 700 to 1141, had no detectable PDE activity. All mutant proteins were expressed as determined by Western blot analysis. These findings localize the PDE3A catalytic domain to within amino acid residues 679 to 1141.

The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein

Science ◽  
2019 ◽  
Vol 364 (6438) ◽  
pp. 389-394 ◽  
Author(s):  
Chao Qi ◽  
Simona Sorrentino ◽  
Ohad Medalia ◽  
Volodymyr M. Korkhov
Keyword(s):  
G Protein ◽  
Catalytic Domain ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Bound State ◽  
Adenylyl Cyclases ◽  
Cellular Processes ◽  
Allosteric Sites ◽  
Stimulatory G Protein ◽  
Dependent Signal

Membrane-integral adenylyl cyclases (ACs) are key enzymes in mammalian heterotrimeric GTP-binding protein (G protein)–dependent signal transduction, which is important in many cellular processes. Signals received by the G protein–coupled receptors are conveyed to ACs through G proteins to modulate the levels of cellular cyclic adenosine monophosphate (cAMP). Here, we describe the cryo–electron microscopy structure of the bovine membrane AC9 bound to an activated G protein αs subunit at 3.4-angstrom resolution. The structure reveals the organization of the membrane domain and helical domain that spans between the membrane and catalytic domains of AC9. The carboxyl-terminal extension of the catalytic domain occludes both the catalytic and the allosteric sites of AC9, inducing a conformation distinct from the substrate- and activator-bound state, suggesting a regulatory role in cAMP production.

scholarly journals Correction: Synthesis, chiral resolution, absolute configuration assignment and pharmacological evaluation of a series of melatoninergic ligands

MedChemComm ◽  
2014 ◽  
Vol 5 (10) ◽  
pp. 1590-1590
Author(s):  
Mohamed Ettaoussi ◽  
Basile Pérès ◽  
Christian Jarry ◽  
Viviane Pallage ◽  
Olivier Nosjean ◽  
...  
Keyword(s):  
Absolute Configuration ◽  
Chiral Resolution ◽  
Pharmacological Evaluation ◽  
Configuration Assignment

scholarly journals Complex roles of cAMP–PKA–CREB signaling in cancer

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Hongying Zhang ◽  
Qingbin Kong ◽  
Jiao Wang ◽  
Yangfu Jiang ◽  
Hui Hua
Keyword(s):  
Target Genes ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Signaling ◽  
Cancer Cell Growth ◽  
Downstream Effectors ◽  
Element Binding Protein ◽  
Responsive Element ◽  
Tumor Types ◽  
Camp Responsive Element Binding

AbstractCyclic adenosine monophosphate (cAMP) is the first discovered second messenger, which plays pivotal roles in cell signaling, and regulates many physiological and pathological processes. cAMP can regulate the transcription of various target genes, mainly through protein kinase A (PKA) and its downstream effectors such as cAMP-responsive element binding protein (CREB). In addition, PKA can phosphorylate many kinases such as Raf, GSK3 and FAK. Aberrant cAMP–PKA signaling is involved in various types of human tumors. Especially, cAMP signaling may have both tumor-suppressive and tumor-promoting roles depending on the tumor types and context. cAMP–PKA signaling can regulate cancer cell growth, migration, invasion and metabolism. This review highlights the important roles of cAMP–PKA–CREB signaling in tumorigenesis. The potential strategies to target this pathway for cancer therapy are also discussed.

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