ABSTRACT
Eribulin is a synthetic microtubule dynamics inhibitor that was developed from a marine natural product halichondrin B. It exhibited in vitro and in vivo activities against a wide number of malignancies. A number of advanced phase trials showed improved survival following eribulin treatment in pretreated advanced breast cancer patients. This review provides an overview of the background to the therapeutic use of eribulin in oncology, including its pharmacology, pharmacokinetics, clinical efficacy, safety, and potential economic factors.
Subject(s)
Humans , Breast , Breast Neoplasms , Drug Evaluation , Ethers, Cyclic , Furans , Ketones , Macrolides , MicrotubulesABSTRACT
Marine antitumor drugs have been the research focus in the world. Recently, advancement has been made in the investigation of six types of compounds including bryostatin-1, ecteinascidin-743, dolastatin, didemnin B, psammaplin and halichondrin B. In this review, we summarized the recent research progress of the above mentioned marine antitumor drugs and their derivatives. Also, the development tendency of marine antitumor drugs was discussed.
Subject(s)
Animals , Humans , Antineoplastic Agents , Pharmacology , Therapeutic Uses , Apoptosis , Biological Products , Pharmacology , Therapeutic Uses , Bryostatins , Pharmacology , Therapeutic Uses , Cell Line, Tumor , Depsipeptides , Pharmacology , Therapeutic Uses , Dioxoles , Pharmacology , Therapeutic Uses , Disulfides , Pharmacology , Ethers, Cyclic , Pharmacology , Macrolides , Marine Biology , Neoplasms , Drug Therapy , Pathology , Tetrahydroisoquinolines , Pharmacology , Therapeutic Uses , Tyrosine , PharmacologyABSTRACT
We have investigated the inhibitory effect of K-crown (18-crown-6 potassium picrate) on photosystem II (PSII)-enriched membrane fragments and O2-evolving core complexes. K-crown at 2-4 microM inhibits about half the control level of O2-evolution activity in both types of PSII samples. Oxygen-evolution studies demonstrated that the ether works by inactivating the centres and not by interfering with antenna function or energy transfer to the reaction centre. K-crown does not disrupt binding of the extrinsic proteins associated with O2 evolution nor complex with bound Ca2+ or Cl- cofactors, but rather it directly inhibits electron transfer after the tetrameric Mn cluster. Fluorescence studies on active and Tris-treated samples showed that K-crown does not prevent artificial donors from transferring electrons to PSII but like DCMU inhibits on the acceptor side after QA, the primary quinone acceptor. However, the ether is a leaky inhibitor and may also act as a weak donor when the Mn cluster is not present. Oxygen-production experiments using silicomolybdate as an artificial acceptor (which accepts from both pheophytin and QB in PSII membranes) demonstrated that the inhibition is at or near the DCMU site.
Subject(s)
Binding Sites , Chlorophyll/metabolism , Electron Transport/drug effects , Ethers, Cyclic/pharmacology , Ethyldimethylaminopropyl Carbodiimide/pharmacology , Kinetics , Light , Light-Harvesting Protein Complexes , Molybdenum/metabolism , Oxygen/metabolism , Photosynthesis/drug effects , Photosynthetic Reaction Center Complex Proteins/chemistry , Photosystem II Protein Complex , Plant Proteins/metabolism , Silicon Compounds/metabolism , Spinacia oleracea/metabolismABSTRACT
The major spontaneously active serine/threonine (Ser/Thr) protein phosphatase activities in N. crassa wild type (FGSC 424) were type 1 (PP1), type-2A (PP2A) and type-2C (PP2C). PP1 and PP2C predominantly dephosphorylated phosphorylase a and casein, respectively. PP2A acted on both substrates, but was two-fold more active against casein. PPI activity was inhibited by protamine, heparin, okadaic acid (IC50 50 nM) and mammalian inhibitor- 1 (lC50 2 nM). On the other hand, PP2A activity was inhibited by much lower concentrations of okadaic acid (IC50 0.2 nM) and also by protamine, but not by heparin or inhibitor-l. About 80 per cent of total PP1 activity was associated with the particulate fraction and could be partially extracted with 0.5 M NaCl. Seventy and ninety percent of PP2A and PP2C activities, respectively, were found in the soluble fraction. In addition we have partially purified an acid and thermostable PP1 inhibitor which effectively inhibits both N. crassa and mammalian PP1.
Subject(s)
Animals , Rats , Ethers, Cyclic/pharmacology , Phosphoprotein Phosphatases/antagonists & inhibitors , Neurospora crassa/enzymology , Serine/metabolism , Threonine/metabolism , Chromatography , Phosphoprotein Phosphatases/metabolism , Substrate SpecificityABSTRACT
Effect of 1,25,50 and 75 nM of okadaic acid (OA) on human lymphocytes from healthy individuals in culture has been investigated. To our surprise, we observed induction of significantly high sister chromatid exchanges (SCEs) at concentrations known to inhibit both protein phosphatase-1 (PP-1) and protein phosphatase -2A (PP-2A). However, 1 nM okadaic acid, known to inhibit PP-2A alone, did not induce this cellular feature/phenotype. This novel preliminary observation lays foundation for investigating further the role of PP-1 inhibition in governing as yet unknown finer controls in the induction of high SCEs, the mechanism for which has eluded answers till date.
Subject(s)
Cells, Cultured , Enzyme Inhibitors/pharmacology , Ethers, Cyclic/pharmacology , Humans , Lymphocytes/drug effects , Okadaic Acid , Phosphoprotein Phosphatases/antagonists & inhibitors , Protein Phosphatase 1 , Protein Phosphatase 2 , Reference Values , Sister Chromatid Exchange/drug effectsABSTRACT
Stimulation of lamb tracheal smooth muscle fibre strips with endothelin-1 and okadaic acid results in the development of isometric tensions which are long lasting. However, endothelin-1 is more potent constrictor than okadaic acid. An analysis of 20,000 Da regulatory myosin light chain by two-dimensional gel electrophoresis shows an identical phosphorylation pattern.
Subject(s)
Animals , Endothelins/pharmacology , Ethers, Cyclic/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Okadaic Acid , Sheep , TracheaABSTRACT
Se estudió la reactividad de la 9*, 11*-epoxitigogenina y su 12 ß-acetato con HCLO4 70 % y CH3MgI. En la reacción catalizada por ácido, la apertura del anillo oxiránico ocurre solamente si está presente el grupo 12 ß-OAc. Cuando se emplea el ataque nucleofílico directo (CH3MgI), la apertura del epóxido no tiene lugar, aun en presencia de este grupo. En este caso, sin embargo, puede ocurrir la apertura del anillo F del sistema espirocetálico
Subject(s)
Ethers, Cyclic/chemical synthesis , Magnesium , Perchlorates , SteroidsABSTRACT
En este trabajo se presenta la síntesis de algunos éteres cíclicos prostanoides, análogos de la prostaciclina obtenidos partiendo del intermediario PGA2 (extraído del coral blando Plexura homomalla, recolectado en la costa note de Venezuela); conjuntamente con algunas pruebas farmacológicas preminares en el área de inmunología o hematología