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S Ulhaq E C Chinje M A Naylor M Jaffar I J Stratford M D Threadgill 《Bioorganic & medicinal chemistry》1999,7(9):1787-1796
L-Thiocitrulline is a known potent inhibitor of several isoforms of nitric oxide synthase (NOS). To explore the structure-activity relationships (SARs) for this molecule in more depth than has previously been reported, three analogues substituted at the sulphur of the isothioureas have been synthesised. In two of these, the S-substituent was 'tied back' sterically by cyclisation to the nitrogen remote from the amino-acid unit. N(delta)-(4,5-Dihydrothiazol-2-yl)ornithine was identified as an inhibitor of rat inducible and constitutive isoforms of NOS and of a constitutive NOS derived from a human tumour xenograft. Analogous N(delta)-(thiazol-2-yl)ornithines were less active, whereas the corresponding N(delta)-(oxazol-2-yl)ornithine and N(delta)-(pyrimidin-2-yl)ornithine failed completely to inhibit NOS. A new efficient preparation of the critical synthetic intermediate, N(alpha)-Boc-thiocitrulline t-butyl ester, has been developed. Further exploration of the SAR with 2-amino-5-(heterocyclylthio)pentanoic acids (synthesised from 2-(Boc-amino)-5-bromopentanoic acid t-butyl ester), with N-(4-aminobutyl)thiourea and with 2-(4-aminobutylamino)-4,5-dihydrothiazole enabled refinement of our previous model for binding of the substrate, L-arginine, and the inhibitors to NOS. 相似文献
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Mark Bell David Foley Claire Naylor Colin Robinson Jennifer Riley Ola Epemolu Paul Scullion Yoko Shishikura Elad Katz W.H. Irwin McLean Paul Wyatt Kevin D. Read Andrew Woodland 《Bioorganic & medicinal chemistry letters》2018,28(19):3255-3259
The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma. 相似文献
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P. G. D. Naylor 《Journal of applied microbiology》1964,27(3):422-431
S ummary . Proteus spp. formed discrete colonies on a simple nutrient agar. This lack of swarming was neither a function of electrolyte deficiency nor of low osmotic pressure. If electrolytes and certain carbohydrates were added to such a medium the organism swarmed. Growth studies showed that 0.5% (w/v) NaCl or 2.86% (w/v) dulcitol promoted greater growth than 2.9% (w/v) glucose. Amongst the 9 genera tested only Proteus and Serratia grew better in the presence of NaCl. It is suggested that this growth enhancement is a factor in causing Proteus to swarm. 相似文献
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The behaviour of the tompot blenny Parablennius gattorugine was studied from a long‐term underwater photographic record from two sites on the south‐west coast of the U.K. Repeated observations of individually identifiable P. gattorugine during 112 dives revealed that male P. gattorugine may guard eggs in a particular crevice over subsequent breeding seasons, reside in the same location for up to 4 years and recover from injuries received in disputes over territory. Further observations included resident males wiping eggs with greatly expanded anal glands, adult‐type fighting between juveniles and unusual behaviour where a large male manipulated an empty mollusc shell for the attention of two smaller conspecifics. 相似文献
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OBJECTIVE: To describe and illustrate the characteristic features of amyloid in cytologic preparations and point out its diagnostic pitfalls. STUDY DESIGN: Five fine needle aspirates and one bronchial washing that contained amyloid were retrospectively reviewed. The aspirates were obtained from each of the five following sites: lung, occipital lymph node, thyroid gland, proximal humerus and subcutaneous soft tissue. Smears of all of the aspirates were stained with Papanicolaou stain, and in two cases they were also stained with Diff-Quik. Cell block sections were stained with hematoxylin and eosin. Congo red, CD45 and CD20 were used on selected cases. RESULTS: Amyloid appears as either flocculent material or irregularly shaped fragments with scalloped and pointed edges. The amorphous fragments are acellular and frequently associated with connective tissue cells. They stain eosinophilic to cyanophilic with Papanicolaou stain and deep blue with Diff-Quik. In two cases an exuberant giant cell reaction almost obscured the amyloid. In the thyroid aspirate, the amyloid was misinterpreted as colloid. In bronchial washings and lung aspirates, amyloid has to be distinguished from mucus, alveolar proteinosis, chondroid material and corpora amylacea. When circumferentially surrounded by lymphocytes or plasma cells, flocculent amyloid deposits may simulate adenoid cystic carcinoma. CONCLUSION: Amyloid can be easily overlooked or mistaken for other entities with similar staining qualities. Congo red staining can help to confirm the diagnosis. 相似文献
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