Toxicology Research Today is a free monthly online journal that collates and summarizes the latest research about Toxicology, including details on forensic toxicology, carcinogenicity, assays.

Synthesis and evaluation of 1,4-diphenylbutadiene derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) production.

Miyazaki H, Sai H, Ohmizu H, Murakami J, Ohtani A, Ogiku T

Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Co., Ltd, 3-16-89, Kashima, Yodogawa, Osaka 532-8505, Japan.

Butadiene-imide 1 (T-686) derivatives were synthesized and evaluated for their inhibitory activity against PAI-1 production and their ADMET (DMPK and toxicology) profiles. Among these derivatives, compound 15k (T-2639) showed good antithrombotic activity in two rat thrombosis models without affecting bleeding time, indicating reduction of haemorrhagic risk. We also describe in this report a practical synthesis of 15k suitable for scale-up using Z,E-selective Stobbe condensation.

Published 11 March 2010 in Bioorg Med Chem, 18(5): 1968-1979.
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Articles on Toxicology published 11 March 2010:

S-Arachidonoyl-2-thioglycerol synthesis and use for fluorimetric and colorimetric assays of monoacylglycerol lipase.   Bioorg Med Chem, 18(5): 1942-1947.

We report the first synthesis of 2-thioglycerol and S-arachidonoyl-2-thioglycerol (the thioester analog of the endocannabinoid 2-arachidonoylglycerol) in an eight or nine step procedure with a yield of approximately 25% and establish the use of this substrate for maleimide-based fluorescent and dithiobis(2-nitrobenzoic acid)-based colorimetric assays of human recombinant monoacylglycerol (MAG) lipase (hMAGL) and human brain membrane MAG hydrolase activity. Inhibitor structure-activity ... [Abstract] [Full-text]

Gene expression of sHsps, Hsp40 and Hsp60 families in normal and abnormal embryonic development of mouse forelimbs.   Toxicol Lett, 193(3): 242-251.

Heat shock proteins (Hsps) are thought of as chaperones of morphologic development of cells and organisms, and believed to be closely related to normal and abnormal embryonic development. Previous studies only focused on a small number of HSPs and their relationships with embryogenesis, and roles of most HSPs in normal and abnormal embryonic development remain unclear. The present study detected expression of sHsps, Hsp40 and Hsp60 in normal and abnormal development of embryonic forelimbs in ... [Abstract] [Full-text]

Occupational exposure to low levels of benzene: Biomarkers of exposure and nucleic acid oxidation and their modulation by polymorphic xenobiotic metabolizing enzymes.   Toxicol Lett, 193(3): 229-235.

This study investigated nucleic acid oxidation associated with exposure to benzene at low levels in 239 workers recruited among traffic policemen, taxi drivers and gasoline pump attendants of the city of Parma (Italy). Biomarkers of exposure, namely urinary t,t-muconic acid (t,t-MA) and S-phenylmercapturic acid (S-PMA), urinary cotinine, and urinary biomarkers of nucleic acid oxidation, namely 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and ... [Abstract] [Full-text]

Metabolic interactions between ethanol and MDMA in primary cultured rat hepatocytes.   Toxicology.

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy), a drug of abuse commonly consumed at rave parties, is often taken in a polydrug abuse scenario, ethanol being one of the most associated drugs. Both MDMA and ethanol are mainly metabolized in the liver with formation of toxic metabolites. Our working hypothesis is that ethanol can modify the metabolism of MDMA through the cytochrome P450 system, and that this effect may be further potentiated by hyperthermia, a well-known consequence of MDMA ... [Abstract] [Full-text]

Telithromycin blocks neuromuscular transmission and inhibits nAChR currents in vitro.   Toxicol Lett.

Telithromycin, a ketolide antibiotic, is reported to exacerbate myasthenia gravis, potentially leading to respiratory failure and death. However, telithromycin is not associated with neuromuscular effects in animal toxicity studies. The objective of this study was to examine the effect of telithromycin on the neuromuscular junction in the isolated rat phrenic nerve-diaphragm preparation and to investigate its postsynaptic effects on the muscle-like nicotinic acetylcholine (ACh) receptors ... [Abstract] [Full-text]

T(h)1 (CXCL10) and T(h)2 (CCL2) chemokine expression in patients with immune thrombocytopenia.   Hum Immunol.

Immune thrombocytopenia (ITP) is an acquired organ-specific autoimmune disease with a polarization of T(h)1. Both the T(h)1 chemokine CXCL10 and T(h)2 chemokine CCL2 have been studied in several autoimmune diseases, but the status of these chemokines in ITP is still unknown. The aims of this study were to determine the expression of CXCL10 and CCL2 and their receptors, CXCR3 and CCR2, in ITP patients, and to conduct a preliminary study of the pathogenic roles of these factors in ITP. Plasma ... [Abstract] [Full-text]

Heparin-based hydrogel as a matrix for encapsulation and cultivation of primary hepatocytes.   Biomaterials, 31(13): 3596-3603.

Primary hepatocytes are commonly used as liver surrogates in toxicology and tissue engineering fields, therefore, maintenance of functional hepatocytes in vitro is an important topic of investigation. This paper sought to characterize heparin-based hydrogel as a three-dimensional scaffold for hepatocyte culture. The primary rat hepatocytes were mixed with a prepolymer solution comprised of thiolated heparin and acrylated poly(ethylene glycol) (PEG). Raising the temperature from 25 degrees to 37 ... [Abstract] [Full-text]

Structural determinants for calcium mobilization by prostaglandin E(2) and prostaglandin F(2alpha) glyceryl esters in RAW 264.7 cells and H1819 cells.   Prostaglandins Other Lipid Mediat.

2-Arachidonoylglycerol is oxygenated by cyclooxygenase-2 to form prostaglandin glyceryl esters. Previous work in this laboratory has suggested that PGE(2)-G activates a novel G protein-coupled receptor in a murine macrophage-like cell line, RAW 264.7. To probe the structural determinants for the putative receptor in RAW 264.7 cells, a panel of 10 analogs was tested for their ability to increase intracellular calcium. These analogs included PGE(2)- and PGF(2alpha)-ethanolamide, 4 PGE(2) glyceryl ... [Abstract] [Full-text]

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