Conformations and conformational interconversions of diastereomeric cyclic tetraprolines

Cyclic tetrapeptides exclusively composed of L- and D-Pro have been studied by theoretical means (conformational searches and molecular mechanics calculations using the CHARMM program) supported by ¹H-NMR spectroscopy, X-ray analysis and chiroptical measurements. We explored the entire conformational space of the diastereomers cyclo(LLLL-Pro₄) (I), cyc1O(LDLD-Pro₄) (II) and CYClo(LLDD-Pro₄) (III) including the low-energy conformations and the related interconversion paths. The conformational interconversions were found to be restricted to cis/trans isomerisations of the amide bonds. Owing to the polycyclic nature of cyclo(Pro₄) most of the cis/trans transitions are hindered by energy barriers higher than 30 kcal/mol (up to 150–200 kcal/mol). A few transitions are characterized by computed energy barriers comparable to those found in linear -Xxx-Pro- sequences (～ 18 kcal/mol), and are therefore experimentally significant. Experimental evidence has been obtained in the case Of CyClo(LDLD-Pro₄), where two enantiomers are interconverted by a series of 4 cis/trans isomerisations ctct→cttt→tttt→tctt→tctc. The Eyring activation parameters of this reaction were determined in H₂O and in DMF by chiroptical measurements (ΔH^#= 44 and 28 kcal/mol; ΔS^#=59 and 22 cal K ^?1 mol^?1, respectively), and correlated with the calculated barriers. In I and III comparable series of four cis/trans isomerisations relate two main conformations with the peptide bond sequences ctct and tctc. In compound I pseudorotational images are interconverted via ctct→ccct→cctt→cctc→tctc. The pathway ctct→ccct→cctt→cctc→tctc. that relates diastereomeric main conformations of III involves exclusively low-energy intermediates; however, the transitions leading to the all-cis conformation are energetically unfavourable, and the conformational space is divided in three insulated domains.     

Classes of tissue hypoxia

We identify eight causes of tissue hypoxia, falling into three classes, A, B, and C, depending upon the effect on the critical mixed venous p O₂ and the optimal oxygen consumption rate. The critical mixed venous p O₂ is the value above which the oxygen consumption rate is optimal and independent of the mixed venous p O₂ and below which the oxygen consumption rate decreases towards zero. Class A hypoxia: primary decrease in mixed venous p O₂. Causes: 1) ischaemic hypoxia (decrease in cardiac output), 2) low-extractivity hypoxia (decrease in oxygen extraction tension, p ₈). Class B hypoxia: primary increase in critical mixed venous p O₂. Causes: 1) shunt hypoxia (increased a-v shunting), 2) dysperfusion hypoxia (increased diffusion length from erythrocytes to mitochondria and/or decreased total capillary endothelial diffusion area, e. g., tissue oedema, microembolism), 3) histotoxic hypoxia (inhibition of the cytochrome chain). Class C hypoxia: primary increase in optimal oxygen consumption rate. Causes: 1) uncoupling hypoxia (uncoupling of the ATP formation associated with O₂ reduction), 2) hypermetabolic hypoxia (increased energy metabolism, e. g., due to hyperthermia).     

Chronic Inhalation of Short Asbestos Fibers

Chronic Inhalation of Short Asbestos Fibers. PLATEK, S. F.,GROTH, D. H., ULRICH, C. E., STETTLER, L. E., FINNELL, M. S.,AND STOLL, M. (1985). Fundam. Appl. Toxicol. 5, 327–340.An animal inhalation study was initiated to study the chronicbiological effects of inhalation of short chrysotile asbestosfibers. Rats and monkeys were exposed for 18 months, 7 hr/day,5 days/week to a specially prepared, chrysotile asbestos aerosol.Based upon daily chamber measurements, the mean concentrationof fibers in the chamber air was 1.0 mg/m³. By phase contrastmicroscopy, the number of fibers > 5 µm in length wasdetermined to be 0.79 fiber per cubic centimeter. Rats wereautopsied for pathological and histochemical examination at1, 3, 6, 12, 18, and 24 months after initiating exposures. Nosignificnt differences in the histochemical data were seen betweenthe exposed and control groups. Gross and histopathologic examinationof exposed and control groups of rats indicated no compound-relatedlesions, including fibrosis. Open lung biopsies were performedon the chrysotile-exposed and the control monkeys 28 monthsafter initiating exposures. Histopathologic evaluation of thelung biopsy tissue showed the presence of asbestos bodies adjacentto the terminal bronchioles of the asbestos-exposed monkeys.There was no observed fibrosis in pulmonary tissue. All monkeysare being maintained for an indefinite period and observed forsigns of latent pulmonary disease.