Purine derivatives as competitive inhibitors of human erythrocyte membrane phosphatidylinositol 4-kinase.

The possibility of deriving a potent, cell-penetrating inhibitor of human erythrocyte PI 4-kinase, competitive with respect to ATP, has been investigated in a series of purine derivatives and analogues. The purine nucleus is not essential for binding to the ATP site but offers the advantage of synthetic accessibility to its derivatives. The optimum substitution pattern in purine was found to be an electron-releasing substituent in the 6-position (e.g. amino, as in adenine, 1) and a compact, lipophilic group in either the 8-position or, preferably, the 9-position, suggesting the importance of the N-1 lone pair and hydrophobic contributions of the 8- and 9-substituents to binding. The most potent inhibitor synthesized was 9-cyclohexyladenine (54), which has an apparent Ki value of 3.7 microM.

Total synthesis of the four stereoisomers of dihexadecanoyl phosphatidylinositol and the substrate stereospecificity of human erythrocyte membrane phosphatidylinositol 4-kinase.

A new and convenient method for the preparation of the four stereoisomers of dihexadecanoyl phosphatidylinositol has been developed. An enantiomeric pair of acid-labile, pentaprotected myo-inositol building blocks was synthesized in high yield and coupled with chiral phenyl dihexadecanoylglyceryl phosphates to give the fully protected phosphatidylinositols. These were subsequently deprotected by hydrogenolysis and self-hydrolysis in aqueous ethanol to give the desired pure products. Comparison of these compounds as potential substrates for a partially purified phosphatidylinositol 4-kinase (EC 2.7.1.67) derived from human erythrocyte membranes revealed that the chirality of the inositol ring is crucial for efficient phosphorylation, whereas the chirality of the glycerol moiety is relatively unimportant. Moreover, the similarity in phosphorylation rates of the naturally occurring mammalian phospholipid, I, and its synthetic stereochemical counterpart, compound 10a, suggests that the enzyme is relatively tolerant to changes in fatty acid composition.

Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists.

A rational approach to the design of centrally acting agents is presented, based initially upon a comparison of the physicochemical properties of three typical histamine H2 receptor antagonists which do not readily cross the blood-brain barrier with those of the three brain-penetrating drugs clonidine (6), mepyramine (7) and imipramine (8). A good correlation was found between the logarithms of the equilibrium brain/blood concentration ratios in the rat and the partition parameter, delta log P, defined as log P (1-octanol/water)-log P (cyclohexane/water), which suggests that brain penetration might be improved by reducing overall hydrogen-bonding ability. This model has been employed as a guide in the design of novel brain-penetrating H2 antagonists by the systematic structural modification of representatives of different structural types of H2 antagonists. Although marked increases in brain penetration amongst congeners of cimetidine (1), ranitidine (9), and tiotidine (10) were achieved, no compound was found with an acceptable combination of H2 antagonist activity (-log KB in the guinea pig atrium greater than 7.0) and brain penetration (steady-state brain/blood concentration ratio greater than 1.0). Conversely, structural modification of N-[[(piperidinyl-methyl)phenoxy]propy]acetamide (30) led to several potent, novel compounds which readily cross the blood-brain barrier. One of these, zolantidine (SK&F 95282, 41), whose -log KB is 7.46 and steady-state brain/blood ratio is 1.4, has been identified for use in studying histaminergic H2 receptor mechanisms in brain. Comparison of delta log P values with the logarithms of the brain/blood ratios for 20 structurally diverse compounds for which data became available confirms a highly significant correlation and supports the general validity of this model.

Perforation of axillary vein by a branch of the axillary artery: an anatomical study / Perforación de la vena axilar por una rama de la arteria axilar: un estudio anatómico

Anatomical variations in the region of axilla and pectoral region are very common. These variations need attention to avoid complications arising during surgeries and diagnostic and interventional invasive procedures in this region such as surgeries for breast carcinoma, venous access during central venous line, pacemaker and cardiac defibrillator implantation etc. During routine cadaveric dissection we had noticed a rare variation of axillary vein and artery. In this case axillary vein, just deep to the inferior border of pectoralis minor was pierced by the lateral thoracic artery, a branch of axillary artery. Perforation of the axillary vein by a branch of the axillary artery is extremely rare variation encountered till now. We report a variation wherein the lateral thoracic artery a branch of the second part of axillary artery was unusually long and perforated the axillary vein, just posterior to the inferior border of pectoralis minor muscle before supplying the structures in the anterolateral chest wall. Histological findings revealed duplication of lumen at the site of perforation through which the lateral thoracic artery was passing and the surrounding area was sealed by the connective tissue. Sound knowledge of anatomy of axillary and pectoral region may help in reducing complications while doing surgical and diagnostic procedure in these regions.

Las variaciones anatómicas en las regiones axilar y pectoral son muy comunes. Estas variaciones necesitan atención para evitar las complicaciones que surgen durante las cirugías y los procedimientos invasivos de diagnóstico e intervención en esta región, tales como cirugía de cáncer mamario, acceso venoso para una vía venosa central, implantación de marcapasos y desfibrilador, etc. Durante una disección de rutina se evidenció una variación poco frecuente de la vena axilar y arteria axilar. Se presenta una variación en que la arteria torácica lateral, rama de la segunda parte de la arteria axilar, inusualmente larga, perforaba la vena axilar, justo por detrás del margen inferior del músculo pectoral menor, antes de irrigar a las estructuras de la pared torácica anterolateral. La histológía reveló la duplicación del lumen en el sitio de perforación a través del cual pasa la arteria torácica lateral, que periféricamente fue sellada por tejido conectivo. La perforación de la vena axilar por una rama de la arteria axilar es una variación que raramente se observa, por eso un buen nivel de conocimientos de la anatomía de las regiones axilar y pectoral puede ayudar a reducir las complicaciones cuando se realizan procedimientos quirúrgicos y de diagnóstico en estas regiones.