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https://www.readbyqxmd.com/read/29115558/bryostatin-1-causes-attenuation-of-tpa%C3%A2-mediated-tumor-promotion-in-mouse-skin
#1
Ning Zeng, Yi Xu, Yiping Wu, Tang Hongbo, Min Wu
The present study was designed to investigate the tumor inhibitory potential of bryostatin 1 in a 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced mouse model of skin cancer. The radical inhibition potential of various doses of bryostatin 1 was investigated against 2,2‑diphenyl‑1‑picrylhydrazyl (DPPH) bleach in vitro. The DPPH radical potential was observed compared with treatment with 5, 10, 15, 20, 25 and 30 µM doses of bryostatin 1. In vivo, bryostatin 1 prevented the TPA‑mediated increase in the level of H2O2 and myeloperoxidase in mouse epidermal tissue...
November 6, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29109995/total-synthesis-of-7-des-o-pivaloyl-7-o-benzylbryostatin-10
#2
Anthony P Green, Simon Hardy, Alan T L Lee, Eric J Thomas
The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O-pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17-C27 fragment with aldehydes corresponding to the C1-C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1-C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling...
November 15, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29109991/synthetic-approaches-to-the-c11-c27-fragments-of-bryostatins
#3
Anthony P Green, Simon Hardy, Eric J Thomas
The modified Julia reaction and acyl carbanion chemistry, especially reactions of 2-lithiated dithianes, have been investigated for the synthesis of intermediates that are the synthetic equivalents of the C11-C27 fragments of bryostatins. The modified Julia reaction using 2-benzothiazolylsulfones was found to be more useful for the formation of the C16-C17 double-bond than the classical Julia reaction using phenylsulfones, and bulky sulfones gave very good (E)-stereoselectivity. The alkylation of a dithiane monoxide that corresponded to a C19-acyl carbanion using (E)-1-bromobut-2-ene was efficient but the use of a more complex allylic bromide corresponding to the C20-C27 fragment of the bryostatins was unsuccessful, possibly due to competing elimination reactions...
November 15, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29066536/making-bryostatin-1-through-smart-chemistry
#4
(no author information available yet)
Scientists have come up with an efficient, scalable way to chemically synthesize bryostatin 1, a marine-derived natural PKC modulator that has been in scarce supply, impeding a thorough evaluation of its therapeutic potential.
October 24, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29026042/scalable-synthesis-of-bryostatin-1-and-analogs-adjuvant-leads-against-latent-hiv
#5
Paul A Wender, Clayton T Hardman, Stephen Ho, Matthew S Jeffreys, Jana K Maclaren, Ryan V Quiroz, Steven M Ryckbosch, Akira J Shimizu, Jack L Sloane, Matthew C Stevens
Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer's disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year)...
October 13, 2017: Science
https://www.readbyqxmd.com/read/28934369/in-vivo-activation-of-latent-hiv-with-a-synthetic-bryostatin-analog-effects-both-latent-cell-kick-and-kill-in-strategy-for-virus-eradication
#6
Matthew D Marsden, Brian A Loy, Xiaomeng Wu, Christina M Ramirez, Adam J Schrier, Danielle Murray, Akira Shimizu, Steven M Ryckbosch, Katherine E Near, Tae-Wook Chun, Paul A Wender, Jerome A Zack
The ability of HIV to establish a long-lived latent infection within resting CD4+ T cells leads to persistence and episodic resupply of the virus in patients treated with antiretroviral therapy (ART), thereby preventing eradication of the disease. Protein kinase C (PKC) modulators such as bryostatin 1 can activate these latently infected cells, potentially leading to their elimination by virus-mediated cytopathic effects, the host's immune response and/or therapeutic strategies targeting cells actively expressing virus...
September 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28901773/transformation-of-the-b-ring-to-the-c-ring-of-bryostatins-by-csp-3-h-amination-and-z-to-e-isomerization
#7
Ji Lu, Yuebao Zhang, WenYu Yang, Qianyou Guo, Lu Gao, Zhenlei Song
An interesting approach to transform the B ring of bryostatins to the C ring has been developed. The key tactics of the approach feature an intramolecular Csp(3)-H bond amination to form spirocyclic hemiaminal, which undergoes ring opening to afford the C ring found in bryostatin 17. The subsequent epoxidation/oxidation sequence results in Z to E isomerization of the exo-cyclic enoate, delivering the common precursor, which could be transformed into the C ring found in bryostatins 1, 2, 4-9, 12, 14, and 15.
October 6, 2017: Organic Letters
https://www.readbyqxmd.com/read/28684613/endothelial-cell-autophagy-maintains-shear-stress-induced-nitric-oxide-generation-via-glycolysis-dependent-purinergic-signaling-to-endothelial-nitric-oxide-synthase
#8
Leena P Bharath, Jae Min Cho, Seul-Ki Park, Ting Ruan, Youyou Li, Robert Mueller, Tyler Bean, Van Reese, Russel S Richardson, Jinjin Cai, Ashot Sargsyan, Karla Pires, Pon Velayutham Anandh Babu, Sihem Boudina, Timothy E Graham, J David Symons
OBJECTIVE: Impaired endothelial cell (EC) autophagy compromises shear stress-induced nitric oxide (NO) generation. We determined the responsible mechanism. APPROACH AND RESULTS: On autophagy compromise in bovine aortic ECs exposed to shear stress, a decrease in glucose uptake and EC glycolysis attenuated ATP production. We hypothesized that decreased glycolysis-dependent purinergic signaling via P2Y1 (P2Y purinoceptor 1) receptors, secondary to impaired autophagy in ECs, prevents shear-induced phosphorylation of eNOS (endothelial nitric oxide synthase) at its positive regulatory site S1117 (p-eNOS(S1177)) and NO generation...
September 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28673572/elimination-of-cancer-stem-cells-and-reactivation-of-latent-hiv-1-via-ampk-activation-common-mechanism-of-action-linking-inhibition-of-tumorigenesis-and-the-potential-eradication-of-hiv-1
#9
Jahahreeh Finley
Although promising treatments are currently in development to slow disease progression and increase patient survival, cancer remains the second leading cause of death in the United States. Cancer treatment modalities commonly include chemoradiation and therapies that target components of aberrantly activated signaling pathways. However, treatment resistance is a common occurrence and recent evidence indicates that the existence of cancer stem cells (CSCs) may underlie the limited efficacy and inability of current treatments to effectuate a cure...
July 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28638377/a-novel-bromodomain-inhibitor-reverses-hiv-1-latency-through-specific-binding-with-brd4-to-promote-tat-and-p-tefb-association
#10
Huachao Huang, Shuai Liu, Maxime Jean, Sydney Simpson, He Huang, Mark Merkley, Tsuyoshi Hayashi, Weili Kong, Irene Rodríguez-Sánchez, Xiaofeng Zhang, Hailemichael O Yosief, Hongyu Miao, Jianwen Que, James J Kobie, James Bradner, Netty G Santoso, Wei Zhang, Jian Zhu
While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28610952/structural-diversity-of-marine-cyclic-peptides-and-their-molecular-mechanisms-for-anticancer-antibacterial-antifungal-and-other-clinical-applications
#11
REVIEW
Yeji Lee, Chanvorleak Phat, Soon-Cheol Hong
Many cyclic peptides and analogues derived from marine sources are known to possess biological properties, including anticancer, antitumor, antibacterial, antifungal, antiparasitic, anti-inflammation, anti-proliferative, anti-hypertensive, cytotoxic, and antibiotic properties. These compounds demonstrate different activities and modes of action according to their structure such as cyclic oligopeptide, cyclic lipopeptide, cyclic glycopeptide and cyclic depsipeptide. The recent advances in application of the above-mentioned cyclic peptides were reported in dolastatins, soblidotin, didemnin B, aplidine, salinosporamide A, kahalalide F and bryostatin 1 and they are currently in clinical trials...
June 10, 2017: Peptides
https://www.readbyqxmd.com/read/28590053/bryostatin-and-its-synthetic-analog-picolog-rescue-dermal-fibroblasts-from-prolonged-stress-and-contribute-to-survival-and-rejuvenation-of-human-skin-equivalents
#12
Tapan K Khan, Paul A Wender, Daniel L Alkon
Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub-nanomolar concentrations (0.03-0.3 nM), bryostatin-1 and its synthetic analog, picolog (0.1-10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation...
February 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28539614/the-ccr5-antagonist-maraviroc-reverses-hiv-1-latency-in-vitro-alone-or-in-combination-with-the-pkc-agonist-bryostatin-1
#13
María Rosa López-Huertas, Laura Jiménez-Tormo, Nadia Madrid-Elena, Carolina Gutiérrez, Sara Rodríguez-Mora, Mayte Coiras, José Alcamí, Santiago Moreno
A potential strategy to cure HIV-1 infection is to use latency reversing agents (LRAs) to eliminate latent reservoirs established in resting CD4+ T (rCD4+) cells. As no drug has been shown to be completely effective, finding new drugs and combinations are of increasing importance. We studied the effect of Maraviroc (MVC), a CCR5 antagonist that activates NF-κB, on HIV-1 replication from latency. HIV-1-latency models based on CCL19 or IL7 treatment, before HIV-1 infection were used. Latently infected primary rCD4+ or central memory T cells were stimulated with MVC alone or in combination with Bryostatin-1, a PKC agonist known to reverse HIV-1 latency...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28482641/bryostatin-effects-on-cognitive-function-and-pkc%C3%A9-in-alzheimer-s-disease-phase-iia-and-expanded-access-trials
#14
Thomas J Nelson, Miao-Kun Sun, Chol Lim, Abhik Sen, Tapan Khan, Florin V Chirila, Daniel L Alkon
Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28472666/effects-of-chronic-bryostatin-1-on-treatment-resistant-depression-in-rats
#15
Daniel L Alkon, Jarin Hongpaisan, Miao-Kun Sun
Despite over a half-century's intensive research worldwide, the currently available antidepressants remain sub-optimal. Therapeutic options for treatment-resistant depression, for instance, are rather limited. Here, we found that rats exhibited a lasting treatment-resistant depressive immobility in response to open space swim test at a high intensity of induction. The induced depressive behavior is associated with a dramatic impairment in spatial learning and memory. Both the depressive immobility and impairment in spatial learning and memory are sensitive to a period of chronic treatment with bryopstatin-1, a relatively selective activator of protein kinase Cε...
July 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28467486/the-effect-of-ingenol-b-on-the-suppressive-capacity-of-elite-suppressor-hiv-specific-cd8-t-cells
#16
Abena K Kwaa, Kennedy Goldsborough, Victoria E Walker-Sperling, Luiz F Pianowski, Lucio Gama, Joel N Blankson
BACKGROUND: Some latency-reversing agents (LRAs) inhibit HIV-specific CD8+ T cell responses. In a prior study of protein kinase C (PKC) agonists, we found that bryostatin-1 inhibited elite controller/suppressor (ES) CD8+ T cell suppressive activity whereas prostratin had no effect. Ingenol-B is another PKC agonist with potent LRA activity both by itself and in combination with the bromodomain inhibitor JQ1; however its effect on CD8+ T cell mediated control of HIV-1 replication is unknown...
2017: PloS One
https://www.readbyqxmd.com/read/28392275/exploring-the-influence-of-indololactone-structure-on-selectivity-for-binding-to-the-c1-domains-of-pkc%C3%AE-pkc%C3%AE%C2%B5-and-rasgrp
#17
Eleonora Elhalem, Lucía Gandolfi Donadío, Xiaoling Zhou, Nancy E Lewin, Lia C Garcia, Christopher C Lai, James A Kelley, Megan L Peach, Peter M Blumberg, María J Comin
C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins...
June 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28272610/some-limitations-of-an-approach-to-the-assembly-of-bryostatins-by-ring-closing-metathesis
#18
Raphaël Dumeunier, Thomas Gregson, Somhairle MacCormick, Hiroki Omori, Eric J Thomas
Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1-C16 and C17-C27 fragments. However, studies of the formation of the C16-C17 double-bond by RCM were not successful and complex mixtures of products were obtained. To provide an insight into factors that may be involved in hindering RCM in this system, a slightly simplified C1-C16 acid and modified C17-C25 alcohols were prepared and their use for the synthesis of analogues of bryostatins was investigated...
March 8, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28271111/syntheses-of-c17-c27-fragments-of-20-deoxybryostatins-for-assembly-using-julia-and-metathesis-reactions
#19
Matthew Ball, Thomas Gregson, Hiroki Omori, Eric J Thomas
Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol acetates using tributyltin methoxide, with vinylic bromides. The vinylic bromides were prepared using the Sharpless asymmetric dihydroxylation to introduce the hydroxyl groups corresponding to those at C25 and C26 in the bryostatins. Following several steps to introduce alkynyl ester functionality, the stereoselective addition of a tributyltin cuprate followed by tributyltin-bromine exchange gave the required vinylic bromides...
March 8, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28178410/strategies-to-extend-thrombolytic-time-window-for-ischemic-stroke-treatment-an-unmet-clinical-need
#20
REVIEW
Ike Dela Peña, Cesar Borlongan, Guofang Shen, Willie Davis
To date, reperfusion with tissue plasminogen activator (tPA) remains the gold standard treatment for ischemic stroke. However, when tPA is given beyond 4.5 hours of stroke onset, deleterious effects of the drug ensue, especially, hemorrhagic transformation (HT), which causes the most significant morbidity and mortality in stroke patients. An important clinical problem at hand is to develop strategies that will enhance the therapeutic time window for tPA therapy and reduce the adverse effects (especially HT) of delayed tPA treatment...
January 2017: Journal of Stroke
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