1.Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling.
Hiebl J1, Alberts DP, Banyard AF, Baresch K, Baumgartner H, Bernwieser I, Bhatnagar PK, Blanka M, Bodenteich M, Chen T, Esch PM, Kollmann H, Lantos I, Leitner K, Mayrhofer G, Patel R, Rio A, Rovenszky F, Stevenson D, Tubman KD, Undheim K, Weihtrager H, We J Pept Res. 1999 Jul;54(1):54-65.
Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)2-DAS-(Lys)2 (2, SK&F 107647) were investigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2. Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)2-DAS-(Lys(Z)-OBn)2 (6, DAS-2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl-1,1,3,3-tetrameth yluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.
2.The effects of protein kinase C and calmodulin kinase II inhibitors on vestibular compensation in the guinea pig.
Sansom AJ1, Smith PF, Darlington CL, Laverty R. Brain Res. 2000 Nov 3;882(1-2):45-54.
Previous studies have demonstrated that vestibular compensation, the process of behavioural recovery which occurs following unilateral deafferentation of the vestibular labyrinth (UVD), is correlated with changes in in vitro phosphorylation of various protein substrates in the brainstem vestibular nucleus complex (VNC). The aim of the present study was to investigate the possible causal relationship between protein kinase activity and the induction of the vestibular compensation process, by delivering inhibitors of protein kinase C (PKC) or Ca(2+)/calmodulin-dependent kinase II (CaMKII) into the ipsilateral VNC at the time of the UVD and determining their effects on three static symptoms of UVD, spontaneous nystagmus (SN), yaw head tilt (YHT) and roll head tilt (RHT) in guinea pigs. Infusion of the PKC inhibitor, 3-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrr ole-2,5-dione, HCl (bisindolylmaleimide I, HCl/GF 109203X, HCl) ('Bis I'), at a concentration of 5 or 50 microM, significantly increased SN frequency at the earliest time points (6 and 8 h post-UVD) compared to vehicle controls and the less selective analogue, 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (bisindolylmaleimide V) ('Bis V').
