The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Mark T. Hamann - One of the best experts on this subject based on the ideXlab platform.
-
Semisynthetic Latrunculin B Analogs: Studies of Actin Docking Support a Proposed Mechanism for Latrunculin Bioactivity
Bioorganic & medicinal chemistry, 2009Co-Authors: Sucheta Kudrimoti, Safwat A. Ahmed, Pankaj R. Daga, Amir E. Wahba, Sherief I. Khalifa, Robert J. Doerksen, Mark T. HamannAbstract:Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculins A, B and T and 16-epi-Latrunculin B were isolated from the Red Sea sponge Negombata magnifica. N-Alkylated, O-methylated analogs of Latrunculin B were synthesized and biological evaluation was performed for antifungal and antiprotozoal activity. The natural Latrunculins showed significant bioactivity, while the semisynthetic analogs did not. Docking studies of these analogs into the X-ray crystal structure of G-actin showed that, in comparison with Latrunculins A and B, N-alkylated Latrunculins did not dock satisfactorily. This suggests that the analogs do not fit well into the active site of G-actin due to steric clashes and provides an explanation for the absence of bioactivity.
-
Latrunculin with a highly oxidized thiazolidinone ring: structure assignment and actin docking.
Organic letters, 2007Co-Authors: Safwat A. Ahmed, Diaa T. A. Youssef, Pankaj R. Daga, Robert J. Doerksen, Sherief Khalifa, Mostafa K. Mesbah, Srinivas Odde, John J. Bowling, Mark T. HamannAbstract:A new Latrunculin, oxaLatrunculin B (3), was isolated from Red Sea sponge Negombata corticata. Extensive spectroscopic analysis revealed an unprecedented heterocycle in which the rare thiazolidinone ring found in Latrunculins was oxidized with three additional oxygens. An actin polymerization inhibition assay agreed with MM-PBSA free energy calculations that 3 binds more weakly than Latrunculin B to actin. Significant antifungal and anticancer activity of 3 was found, suggesting an alternate target in addition to actin for Latrunculin bioactivity.
-
Quantitative determination of Latrunculins A and B in the Red Sea sponge Negombata magnifica by high performance liquid chromatography
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2006Co-Authors: Sherief Khalifa, Diaa T. A. Youssef, Safwat A. Ahmed, Mostafa K. Mesbah, Mark T. HamannAbstract:Abstract An accurate, reproducible and sensitive method for the quantitative determination of Latrunculins A and B in the organic extract of the Red Sea sponge Negombata magnifica was developed and validated. Latrunculin A and B concentrations were determined by RP-C18-HPLC and a mobile phase consisting of acetonitrile and water (60:40, v/v). The flow rate utilized was 1 mL min −1 and the detector was set at 235 nm. The HPLC analysis of several N. magnifica samples collected from different locations in the Red Sea revealed that Ras Mohamed had the highest concentrations of Latrunculin A, while Safaga had the highest levels of Latrunculin B. Also, a comparison between Latrunculin concentrations in the summer and winter revealed that the yield of Latrunculins were generally higher in the winter.
Germán Sierra-marcuño - One of the best experts on this subject based on the ideXlab platform.
-
Effects of eslicarbazepine acetate on acute and chronic Latrunculin A-induced seizures and extracellular amino acid levels in the mouse hippocampus.
BMC neuroscience, 2014Co-Authors: Germán Sierra-paredes, Germán Sierra-marcuño, Ana I. Loureiro, Lyndon C. Wright, Patrício Soares-da-silvaAbstract:Abstract Background Latrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures. This study tested the effect of eslicarbazepine acetate (ESL), a novel antiepileptic drug, on Latrunculin A-induced acute and chronic seizures, and changes in brain amino acid extracellular levels. Hippocampi of Swiss mice were continuously perfused with a Latrunculin A solution (4 μM, 1 μl/min, 7 h/day) with continuous EEG and videotape recording for 3 consecutive days. Microdialysate samples were analyzed by HPLC and fluorescence detection of taurine, glycine, aspartate, glutamate and GABA. Thereafter, mice were continuously video monitored for two months to identify chronic spontaneous seizures or behavioral changes. Control EEG recordings (8 h) were performed in all animals at least once a week for a minimum of one month. Results Oral administration of ESL (100 mg/kg), previous to Latrunculin A microperfusion, completely prevented acute Latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity. Hippocampal extracellular levels of taurine, glycine and aspartate were significantly increased during Latrunculin A microperfusion, while GABA and glutamate levels remained unchanged. ESL reversed the increases in extracellular taurine, glycine and aspartate concentrations to basal levels and significantly reduced glutamate levels. Plasma and brain bioanalysis showed that ESL was completely metabolized within 1 h after administration to mainly eslicarbazepine, its major active metabolite. Conclusion ESL treatment prevented acute Latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity, supporting a possible anti-epileptogenic effect of ESL in mice.
-
Effect of eslicarbazepine acetate (BIA 2-093) on Latrunculin A-induced seizures and extracellular amino acid concentrations in the rat hippocampus.
Epilepsy research, 2007Co-Authors: Germán Sierra-paredes, Mª Teresa Oreiro-garcía, Mª Dolores Vázquez-illanes, Germán Sierra-marcuñoAbstract:Summary Purpose Eslicarbazepine acetate (ESL, BIA 2-093) is a novel antiepileptic drug endowed with an anticonvulsant potency similar to that of carbamazepine, and shares with carbamazepine and oxcarbazepine the capability to inhibit voltage-gated sodium channels. ESL is efficacious against maximal electroshock seizure-induced seizures, protects against picrotoxin-induced seizures in mice and rats, and prevents development of kindling in rats. In vivo, Latrunculin A microperfusion in the rat hippocampus induces acute epileptic seizures and long-term biochemical changes leading to decreased picrotoxin seizure threshold and spontaneous seizures. We have tested the effect of ESL on Latrunculin A-induced seizures, and its effect on the changes in extracellular amino acid levels induced by Latrunculin A. Methods Rat hippocampus was continuously perfused with a Latrunculin A solution (4μM) through CMA/12 microdialysis probes at a flow rate of 2μl/min during 8h with continuous EEG and videotape recording for 3 consecutive days. The same protocol was repeated after oral administration of ESL (3, 10 and 30mg/kg). Samples from the microdialysate were collected and analyzed by HPLC using pre-column derivatization with 6 aminoquinolyl- N -hydroxysuccinimidyl carbamate (AQC) and fluorescence detection. Results After the administration of 3mg/kg of ESL, seizures were completely suppressed in the 66.7% of the rats. 10 and 30mg/kg of ESL did completely suppressed seizures in the 100% of the animals studied. Hippocampal extracellular levels of glutamate, glycine and aspartate were significantly increased during Latrunculin A microperfusion, while GABA levels remained unchanged. At the doses studied, ESL reversed the increases in extracellular glutamate and aspartate concentrations to basal levels and significantly reduced glycine levels. Conclusions ESL, at oral doses of 3, 10 and 30mg/kg, shows an excellent anticonvulsant effect against seizures induced by Latrunculin A microperfusion in the rat, and prevents the increases in glutamate and aspartate induced by Latrunculin A.
-
Changes in extracellular amino acid concentrations in the rat hippocampus after in vivo actin depolymerization with Latrunculin A.
Neurochemistry international, 2007Co-Authors: Mª Teresa Oreiro-garcía, Mª Dolores Vázquez-illanes, Germán Sierra-paredes, Germán Sierra-marcuñoAbstract:The effect of Latrunculin A microperfusion on hippocampal extracellular concentrations of glutamate, aspartate, glycine and GABA, as measured by in vivo microdialysis, was investigated. Latrunculin A (4 microg/ml) was perfused for three consecutive days (8h a day) to promote in vivo F-actin depolymerization. Intrahippocampal Latrunculin A microdialysis induced seizures during the second and third day of perfusion, and the animals started showing spontaneous seizures 1 month after lartrunculin A administration. Hippocampal glutamate levels were significantly increased during the first day of Latrunculin A microperfusion without significant changes during the second and third day of perfusion. Aspartate levels were significantly increased during the first and second days of treatment. The rise on glutamate and asparate levels was partially reversed by perfusion of NMDA antagonist MK-801. Glycine concentrations were significantly increased during the 3 days of Latrunculin A microdialyis, but no significant effect was observed on baseline GABA levels. One month after Latrunculin A microperfusion, no significant differences in glutamate and aspartate extracellular concentrations were detected as compared to controls, however, significant increases in glycine and GABA extracellular concentrations were observed. The immediate increases in glutamate, aspartate and glycine levels indicate a modulatory effect of the F-actin cytoskeleton on extracellular concentrations of glutamate, aspartate and glycine. The chronic elevations in GABA and glycine levels are more likely to be related with long-term epileptogenesis processes. Our results suggest that the in vivo biochemical study of actin-dependent processes seems to be a promising approach to the neuropathology and neuropharmacology of epileptic seizures.
-
Seizures induced by in vivo Latrunculin a and jasplakinolide microperfusion in the rat hippocampus.
Journal of molecular neuroscience : MN, 2006Co-Authors: Germán Sierra-paredes, Teresa Oreiro-garcía, Alejandra Núñez-rodriguez, Araceli Vázquez-lópez, Germán Sierra-marcuñoAbstract:The molecular basis for developing epilepsy remains under debate. It is hypothesized that increased excitatory synaptic activity might activate the N-methyl-D-aspartate receptor/Ca2+ transduction pathway, which induces long-lasting plasticity changes leading to recurrent epileptiform discharges. To determine if these effects are caused by disruption of F-actin in the dendritic spines, we have perfused the hippocampus of conscious rats with the F-actin-depolymerizing agent Latrunculin A and the actin filament stabilizer jas plakinolide. Single perfusions of Latrunculin A and jasplakinolide decrease and increase picrotoxin seizure threshold, respectively. Repeated perfusions of both Latrunculin A and jasplakinolide induce epileptic seizures and a long-term increase in neuronal excitability. These results suggest that actin disruption might not be just a consequence but also a possible cause of epileptic seizures. We propose a new experimental model in rats to study the biochemical changes that might lead to chronic seizures and a method for testing new antiepileptic drugs.
-
Seizures induced by microperfusion of glutamate and glycine in the hippocampus of rats pretreated with Latrunculin A
Neuroscience letters, 2005Co-Authors: Araceli Vázquez-lópez, Germán Sierra-paredes, Germán Sierra-marcuñoAbstract:Abstract Changes in the membrane distribution of N -methyl- d -aspartate (NMDA) glutamate receptors seem to produce dramatic modifications in neuronal excitability and other properties of the neuron. In order to determine in vivo if these effects are due to the binding of extracellular glutamate and glycine to NMDA extrasynaptic receptors, we perfused the hippocampus of freely moving rats with the actin depolymerizant agent Latrunculin A (4 μM) through microdialysis probes. One month later, continuous microperfusion of glutamate (1 mM) or glycine (1 mM) was used to induce epileptic seizures in the animals pretreated with Latrunculin A. Glutamate microperfusion induced seizures in 50% of the animals studied, and glycine induced seizures in 75% of the rats. However, no effect was observed on control rats, or on those animals previously treated with picrotoxin. Simultaneous microperfusion of 100 μM MK-801 significantly reduced the number and duration of seizures induced by both glutamate and glycine. This study demonstrates that the application of Latrunculin A results in long-term changes in susceptibility to the epileptogenic action of glutamate and glycine.
Diaa T. A. Youssef - One of the best experts on this subject based on the ideXlab platform.
-
3D-QSAR studies of Latrunculin-based actin polymerization inhibitors using CoMFA and CoMSIA approaches
European journal of medicinal chemistry, 2010Co-Authors: Mohammad A. Khanfar, Diaa T. A. Youssef, Khalid A. El SayedAbstract:The marine-derived macrolide Latrunculins A and B, from the Red Sea sponge Negombata magnifica, are known to reversibly bind actin monomers, forming 1:1 complex with G-actin, disrupting its polymerization. Latrunculins have remarkable physiological properties and widely used as biochemical markers. Nevertheless, no QSAR studies have been developed for any kind of actin disruptors. In the present study, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) implemented in the SYBYL software packages were used to develop predictive 3D-QSAR models. Two alignment strategies were used to fit analyzed molecules to a suitable conformational template. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA results presented cross-validated correlation coefficient values (q 2 ) of 0.621 and 0.659, and non-cross-validated values (r 2 ) of 0.938and 0.965, respectively. Comparable to multifit-derived models, CoMFA and CoMSIA 3D-QSAR models were also derived using a molecular alignment obtained by docking Latrunculin derivatives into the ATP active site of actin. In addition to q 2 , the predictive ability was validated using external test set of five compounds. The results of this study suggest that the established model has a strong predictive ability and can be prospectively used in the molecular design and action mechanism analysis of this kind of cytotoxic compounds.
-
Semisynthetic Latrunculin Derivatives as Inhibitors of Metastatic Breast Cancer: Biological Evaluations, Preliminary Structure–Activity Relationship and Molecular Modeling Studies
ChemMedChem, 2010Co-Authors: Mohammad A. Khanfar, Diaa T. A. Youssef, Khalid A. El SayedAbstract:The microfilament cytoskeleton protein actin plays important role in cell biology and can affect cytokinesis, morphogenesis, and cell migration. These functions usually fail and become abnormal in cancer cells. The marine-derived macrolide Latrunculins A and B, from the Red Sea sponge Negombata magnifica, are known to reversibly bind actin monomers, forming 1:1 complex with G-actin, disrupting its polymerization. To identify novel therapeutic agents for effective treatment of metastatic breast cancer, several semisynthetic derivatives of Latrunculin A (1) with diverse steric, electrostatic, hydrogen bond donor and acceptor properties were rationally prepared. Analogues were designed to modulate the binding affinity toward G-actin. Examples of these reactions are esterification, acetylation, and N-alkylation. Semisynthetic Latrunculins were then tested for their ability to inhibit pyrene-conjugated actin polymerization, and subsequently for their antiproliferative, and anti-invasive properties against MCF7 and MDA-MB-231 cells using MTT and invasion assays, respectively.
-
semisynthetic Latrunculin derivatives as inhibitors of metastatic breast cancer biological evaluations preliminary structure activity relationship and molecular modeling studies
ChemMedChem, 2010Co-Authors: Mohammad A. Khanfar, Diaa T. A. Youssef, Khalid El A SayedAbstract:The microfilament cytoskeleton protein actin plays important role in cell biology and can affect cytokinesis, morphogenesis, and cell migration. These functions usually fail and become abnormal in cancer cells. The marine-derived macrolide Latrunculins A and B, from the Red Sea sponge Negombata magnifica, are known to reversibly bind actin monomers, forming 1:1 complex with G-actin, disrupting its polymerization. To identify novel therapeutic agents for effective treatment of metastatic breast cancer, several semisynthetic derivatives of Latrunculin A (1) with diverse steric, electrostatic, hydrogen bond donor and acceptor properties were rationally prepared. Analogues were designed to modulate the binding affinity toward G-actin. Examples of these reactions are esterification, acetylation, and N-alkylation. Semisynthetic Latrunculins were then tested for their ability to inhibit pyrene-conjugated actin polymerization, and subsequently for their antiproliferative, and anti-invasive properties against MCF7 and MDA-MB-231 cells using MTT and invasion assays, respectively.
-
Latrunculin A and its C-17-O-carbamates inhibit prostate tumor cell invasion and HIF-1 activation in breast tumor cells.
Journal of natural products, 2008Co-Authors: Khalid A. El Sayed, Diaa T. A. Youssef, Mohammad A. Khanfar, Hassan M. Shallal, Anbalagan Muralidharan, Bhushan Awate, Yang Liu, Yu-dong Zhou, Dale G. Nagle, Girish V. ShahAbstract:Latrunculin A (1) and B are macrolides reported by Kashman and coworkers from the Red Sea sponge Negombata magnifica Kelly-Borges and Vacelet (Podospongiidae).1 Latrunculins are reported to decrease intraocular pressure and increase outflow facility without corneal effects in monkeys.2,3 Latrunculin B and analogs showed antiangiogenic, antimetastatic, and antimicrobial activities.4 The most important biological effects of Latrunculins are their abilities to disrupt microfilament organization and inhibit microfilament-mediated processes without affecting the organization of the microtubular system.5 The Latrunculins bind reversibly to the cytoskeleton actin monomers, forming 1:1 complexes with G-actin and disrupting polymerization.5 Actin-active agents are attracting more attention in the field of cancer chemotherapy because microfilament and microtubule proteins form versatile dynamic polymers that can define cell polarity, organize cytoplasmic organelles, control cell shape and promote stable cell-cell and cell-matrix adhesions, and generate protrusive forces required for migration.6–8 These functions usually fail and become abnormal in cancer cells. 6–8 Based on X-ray crystallography, the binding site of 1 has been located between subdomains II and IV, in the vicinity of the ATP binding cleft of the protein target in the actin monomer.9,10 The binding pharmacophores of 1 to G-actin were identified as follows: C-1 carbonyl oxygen through water to glutamate 214 carboxy, C-17 lactol hydroxyl to arginine 210 NH (major binding), C-17 pyran oxygen to tyrosine 69 hydroxy, thiazolidinone NH to aspartate 157 carboxy, and thiazolidinone C-20 carbonyl oxygen to threonine 186 hydroxy.9,10 Only the thiazolidinone NH group acts as a hydrogen bonding donor while the rest of the binding functions act as hydrogen bonding acceptors.9,10 Semi-synthetic carbamoylation products of the C-17 lactol group in 1 were produced to study the pharmacological effects of the addition of hydrogen bond donors and acceptors at this key position. This study reports the anti-invasive and HIF-1 inhibitory activities of Latrunculin A (1) and its semi-synthetic analogs (2–6).
-
Latrunculin with a highly oxidized thiazolidinone ring: structure assignment and actin docking.
Organic letters, 2007Co-Authors: Safwat A. Ahmed, Diaa T. A. Youssef, Pankaj R. Daga, Robert J. Doerksen, Sherief Khalifa, Mostafa K. Mesbah, Srinivas Odde, John J. Bowling, Mark T. HamannAbstract:A new Latrunculin, oxaLatrunculin B (3), was isolated from Red Sea sponge Negombata corticata. Extensive spectroscopic analysis revealed an unprecedented heterocycle in which the rare thiazolidinone ring found in Latrunculins was oxidized with three additional oxygens. An actin polymerization inhibition assay agreed with MM-PBSA free energy calculations that 3 binds more weakly than Latrunculin B to actin. Significant antifungal and anticancer activity of 3 was found, suggesting an alternate target in addition to actin for Latrunculin bioactivity.
Motoji Kawasaki - One of the best experts on this subject based on the ideXlab platform.
-
total synthesis of Latrunculin a an ichthyotoxic metabolite of the sponge latrunculia magnifica and its c 15 epimer
Journal of Organic Chemistry, 1992Co-Authors: James D. White, Motoji KawasakiAbstract:Latrunculin A (1), an icthyotoxic metabolite of the sponge Latrunculia maginifica with potent inhibitory action on microfilament-mediated proccesses involved in cell division, was synthesized via a convergent approach. Contruction of a major segment of the Latrunculin ackbone was accomplished by means of a three-component coupling of aldehyde 24,β-keto ester 27, and phosphonium salt 26, which established the conjugated E,Z-diene moiety of 31
-
Total synthesis of (+)-Latrunculin A, an ichthyotoxic metabolite of the sponge Latrunculia magnifica and its C-15 epimer
The Journal of Organic Chemistry, 1992Co-Authors: James D. White, Motoji KawasakiAbstract:Latrunculin A (1), an icthyotoxic metabolite of the sponge Latrunculia maginifica with potent inhibitory action on microfilament-mediated proccesses involved in cell division, was synthesized via a convergent approach. Contruction of a major segment of the Latrunculin ackbone was accomplished by means of a three-component coupling of aldehyde 24,β-keto ester 27, and phosphonium salt 26, which established the conjugated E,Z-diene moiety of 31
Safwat A. Ahmed - One of the best experts on this subject based on the ideXlab platform.
-
Differential binding of Latrunculins to G-actin: a molecular dynamics study.
Journal of chemical information and modeling, 2013Co-Authors: Mohamed A. Helal, Sherief Khalifa, Safwat A. AhmedAbstract:Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculin A (1), Latrunculin B (2), 16-epi-Latrunculin B (3), and Latrunculin T (4) were isolated from the Red Sea sponge Negombata magnifica. In the present study, after testing compounds 2–4 for cytotoxic activity, they were docked into the crystal structure of G-actin and subjected to binding energy calculation and a 20 ns MD simulation. The modeling study shows that Latrunculins binding depends on both hydrophobic interaction of the macrocycle as well as H bonding of the thiazolidinone ring with Asp157 and Thr186. It was noticed that epimerization at C16 of Latrunculin B was well tolerated as it could form an alternative H bonding network. However, opening of the macrocyclic ring deteriorates the actin binding due to reduced hydrophobicity. MD simulation showed that Latrunculin B (2) possesses a more significant stabilizing effect on G-actin than Latrunculin T (4) and could efficiently hinder the flattening transition of G-actin ...
-
Semisynthetic Latrunculin B Analogs: Studies of Actin Docking Support a Proposed Mechanism for Latrunculin Bioactivity
Bioorganic & medicinal chemistry, 2009Co-Authors: Sucheta Kudrimoti, Safwat A. Ahmed, Pankaj R. Daga, Amir E. Wahba, Sherief I. Khalifa, Robert J. Doerksen, Mark T. HamannAbstract:Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculins A, B and T and 16-epi-Latrunculin B were isolated from the Red Sea sponge Negombata magnifica. N-Alkylated, O-methylated analogs of Latrunculin B were synthesized and biological evaluation was performed for antifungal and antiprotozoal activity. The natural Latrunculins showed significant bioactivity, while the semisynthetic analogs did not. Docking studies of these analogs into the X-ray crystal structure of G-actin showed that, in comparison with Latrunculins A and B, N-alkylated Latrunculins did not dock satisfactorily. This suggests that the analogs do not fit well into the active site of G-actin due to steric clashes and provides an explanation for the absence of bioactivity.
-
Latrunculin with a highly oxidized thiazolidinone ring: structure assignment and actin docking.
Organic letters, 2007Co-Authors: Safwat A. Ahmed, Diaa T. A. Youssef, Pankaj R. Daga, Robert J. Doerksen, Sherief Khalifa, Mostafa K. Mesbah, Srinivas Odde, John J. Bowling, Mark T. HamannAbstract:A new Latrunculin, oxaLatrunculin B (3), was isolated from Red Sea sponge Negombata corticata. Extensive spectroscopic analysis revealed an unprecedented heterocycle in which the rare thiazolidinone ring found in Latrunculins was oxidized with three additional oxygens. An actin polymerization inhibition assay agreed with MM-PBSA free energy calculations that 3 binds more weakly than Latrunculin B to actin. Significant antifungal and anticancer activity of 3 was found, suggesting an alternate target in addition to actin for Latrunculin bioactivity.
-
Quantitative determination of Latrunculins A and B in the Red Sea sponge Negombata magnifica by high performance liquid chromatography
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2006Co-Authors: Sherief Khalifa, Diaa T. A. Youssef, Safwat A. Ahmed, Mostafa K. Mesbah, Mark T. HamannAbstract:Abstract An accurate, reproducible and sensitive method for the quantitative determination of Latrunculins A and B in the organic extract of the Red Sea sponge Negombata magnifica was developed and validated. Latrunculin A and B concentrations were determined by RP-C18-HPLC and a mobile phase consisting of acetonitrile and water (60:40, v/v). The flow rate utilized was 1 mL min −1 and the detector was set at 235 nm. The HPLC analysis of several N. magnifica samples collected from different locations in the Red Sea revealed that Ras Mohamed had the highest concentrations of Latrunculin A, while Safaga had the highest levels of Latrunculin B. Also, a comparison between Latrunculin concentrations in the summer and winter revealed that the yield of Latrunculins were generally higher in the winter.