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At least 19 recordsLinked to original sources
PubMed1976

Diacridines: bifunctional intercalators. I. Chemistry, physical chemistry and growth inhibitory properties.

The synthesis, as well as the rationale for synthesis of diacridines, double intercalators, as potential inhibitors of nucleic acid synthesis is presented. The syntheses of (9-acridyl)-putrescine and -spermine, and bis(-9-acridyl)-putrescine, -spermidine, -spermine diamines and of bis(6-chloro-2-methoxy-9-acridyl)-putrescine and -spermine diamines, all substituted on the terminal NH2 groups are described. In addition, the homologous series of diacridines connected by the amino groups of the diamines NH2(CH2)nNH2 (where n = 2,3,4,6,8,10,12,14,16,18) to the C-9 of the diacridines has been synthesized. The chemical properties of these compounds as well as their molecular relationship to DNA are presented. The effect of the double intercalators on the Tm of DNA and of (A)n - (U)n, (dA)n - (dT)n, (G)n - (C)n and on (dG)n - (dC)n have been determined. The double acridine intercalators produce a much greater increase of the Tm of these nucleic acids than do the single acridine intercalators. They also profoundly affect the Tm of DNA in physiological salt concentrations; under these latter conditions the single intercalators have no effect. The relationship between the length of the chain connecting the two acridine rings and the inhibition of the growth of P-388 cells in vitro and vivo is presented. Their growth inhibitory properties appear, in general, to parallel their intercalative abilities.

Acridines↗
PubMed1992

Use of physical chemistry and in vivo exposure to investigate the toxicity of formaldehyde bound to carbonaceous particles in the murine lung.

Knowledge about the health effects of exposure to formaldehyde associated with automotive emissions is of pivotal importance in the risk assessment of this agent. Mobile sources emit many combustion-derived pollutants, including formaldehyde, in association with respirable carbon particles. Because it is hydrophilic, most of the inhaled formaldehyde is absorbed in the upper respiratory tract. However, if the organic vapor is adsorbed on respirable particles, formaldehyde may be deposited in the deep lung with the inhaled particles and may be available to interact adversely with cells along the lung parenchyma. On the respiratory surface, the alveolar macrophage phagocytic system plays the pivotal role in defending the lung against infectious agents. Susceptibility to respiratory infections is a relevant and sensitive indicator of the adverse effects of air pollution because acute and chronic exposures to a variety of air pollutants have been shown to decrease pulmonary antibacterial defenses. The goal of this research was to investigate whether exposure to formaldehyde decreases resistance to respiratory infections through dysfunctions of the alveolar macrophage phagocytic system. The study also explored whether interactions between formaldehyde and respirable carbon black particles alter susceptibility to respiratory infections and impairment of alveolar macrophage phagocytosis by delivering adsorbed formaldehyde to the deep lung with the inhaled particles. A carbon black, Regal GR, was used in these studies as a surrogate for the carbonaceous core of Diesel particulate matter. This material was selected to represent the worst-case scenario because the carbon black was expected to adsorb formaldehyde strongly. To accomplish this goal, mice were exposed to formaldehyde and to carbon black and formaldehyde combinations; increased susceptibility to respiratory infections was quantified by alveolar macrophage-dependent intrapulmonary killing of Staphylococcus aureus after an inhalation challenge with the bacterium. The salient findings of the bactericidal studies are as follows: Fifteen parts per million (ppm)* formaldehyde impaired the intrapulmonary killing of S. aureus when exposure followed the bacterial challenge. One ppm formaldehyde impaired the intrapulmonary killing of S. aureus when exposure preceded and was continued after the bacterial challenge. Coexposures to target concentrations of 3.5 mg/m3 carbon black and 2.5 ppm formaldehyde, or 10 mg/m3 carbon black and 5 ppm formaldehyde after the bacterial challenge had no effect on the intrapulmonary killing of S. aureus. Preexposure for four hours per day for four days to target concentrations of 3.5 mg/m3 carbon black and 2.5 ppm formaldehyde had no effect on the intrapulmonary killing of S. aureus when the assay was performed one day after the cessation of exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1977

The relative role of "A" level chemistry, physics and biology in the medical course.

The performance of 209 students in the 2nd MBBS, first clinical year and final MBBS examinations has been compared retrospectively with their grades in chemistry, physics and biology at "A" level. The mean grade has also been determined for students from different social classes and secondary education. Significant differences in marks for biology were found between successful and not so successful students, especially in the pre-clinical part of the course. Significnat differences in marks and significant correlations were also found for physics but not to any great extent for chemistry. The relative role of these three basic sciences in the medical course is discussed. The suggestion is made that there is a need for a re-appraisal of the privleged position of chemistry and an unquestioned science requirement for entry to medical school.

Biology↗
PubMed1976

Physical chemistry of the lipids of human atherosclerotic lesions. Demonstration of a lesion intermediate between fatty streaks and advanced plaques.

95 individual human atherosclerotic lesions from 26 persons were classified into three groups under the dissecting microscope: fatty streaks, fibrous plaques, and gruel (atheromatous) plaques. Each lesion was isolated by microdissection, its lipid composition determined by chromatography, and the physical states of the lipids identified by polarizing microscopy and in some cases by X-ray diffraction. The composition of each lesion was plotted on the in vitro phase diagram of the major lipids of plaques: cholesterol, cholesterol ester, and phospholipid. The observed physical states were compared with those predicted by the location of the lipid composition on the phase diagram. The most severe lesions (gruel plaques) had an average lipid composition of cholesterol 31.5+/-1.9%, cholesterol ester 47.2+/-2.3%, and phospholipid 15.3+/-0.5%. Their compositions fell within the three-phase zone of the phase diagram, predicting the lipids to be separated into a cholesterol crystal phase, a cholesterol ester oily phase and a phospholipid liquid crystalline phase. In addition to the phospholipid liquid crystalline phase of membranes and myelin-like figures demonstrable by electron microscopy, polarizing microscopy revealed the other two predicted phases, isotropic cholesterol ester-rich droplets and cholesterol crystals. X-ray diffraction studies verified the identity of the crystals as cholesterol monohydrate. Fibrous plaques also had an average lipid composition within the three-phase zone of the phase diagram. Polarizing microscopy revealed the presence of cholesterol monohydrate crystals and lipid droplets in all of these lesions; the droplets were predominately isotropic in 28 of the 31 fibrous plaques. Although these lesions had less free cholesterol and more cholesterol ester than gruel plaques, they were otherwise similar. Fatty streaks had compositions within both the two- and three-phase zones of the phase diagram. Compared with gruel plaques, the fatty streaks within the two-phase zone, defined as "ordinary," had more cholesterol ester, less free cholesterol, a higher cholesteryl oleate/cholesteryl linoleate ratio, a lower sphingomyelin/lecithin ratio, more anisotropic lipid droplets, and rare or no cholesterol crystals. Those lesions within the three-phase zone had many chemical and physical features intermediate between ordinary fatty streaks and gruel plaques. Moreover, 68% of these "intermediate" lesions had no cholesterol crystals by polarizing microscopy in spite of their compositions being within the three-phase zone, indicating the cholesterol ester oily phase or the phospholipid phase or both were supersaturated with cholesterol. Identification of this group of intermediate lesions provides evidence that some fatty streaks may be precursors of advanced plaques.

Adult↗
PubMed1978

The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man.

We determined the maximum solubilities of cholesterol in aqueous conjugated bile salt-egg lecithin-cholesterol systems as a function of several physical-chemical variables including those of physiological importance employing phase equilibria techniques. Equilibration rates are influenced by time and the method of sample preparation in that metastable supersaturation is readily induced at high bile salt: lecithin ratios, and equilibrium saturation by dissolution is achieved sluggisly at low bile salt:lecithin ratios. Equilibrium values for cholesterol saturation vary with the bile salt species, bile salt: lecithin ratio, temperature, ionic strength, and, in particular, with the total concentration of biliary lipids. Within physiological bile salt:lecithin ratios at 37 degreesC the influence of bile salt type and ionic strength is small, whereas the effects of bile salt:lecithin ratio and the total lipid concentration are major factors. We plotted on triangular coordinates a family of cholesterol solubility curves for each total lipid concentration (0.30--30 g/dl) and computed fifth-degree polynomial equations for each curve. With both the curves and the polynomial equations the "per cent cholesterol saturation" of fasting gallbladder and hepatic biles from patients with and without gallstones was calculated and both methods gave similar values. These results deomonstrate that by employing cholesterol saturation values appropriate to the total lipid concentration (range 0.2--24.9 g/dl) of individual biles, all cholesterol stone patients have supersaturated gallbladder biles, (mean, 132% [normal weight individuals], and 199% [morbidly obese individuals]). With controls and pigment stone patients the mean values were 95 and 98%, respectively, and in both approximately 50% of biles were supersaturated. Fasting hepatic biles were significantly more supersaturated than gallbladder biles (means 228--273%). Cholesterol monohydrate crystals were found in the majority of gallbladder (83%) and hepatic (58%) biles of cholesterol gallstone patients but were not observed in pigment stone patients or controls. We conclude that of the several factors in addition to the bile salt:lecithin ratios which can influence the cholesterol saturation of bile the total lipid concentration is the predominant determinant physiologically. Our results demonstrate that (a) metastable supersaturation is frequent in both normal and abnormal biles, (b) cholesterol gallstone patients have supersaturated gallbladder and hepatic biles without exception, and (c) the predominant driving force for cholesterol precipitation appears to be the absolute degree of cholesterol supersaturation.

Bile↗
PubMed1977

Single and multiple turnover reactions in the ubiquinone-cytochrome b-c2 oxidoreductase of Rhodopseudomonas sphaeroids: the physical chemistry of the major electron donor to cytochrome c2, and its coupled reactions.

We have examined the thermodynamic properties of the physiological electron donor to ferricytochrome c2 in chromatophores from the photosynthetic bacterium Rhodopseudomonas sphaeroides. This donor (Z), which is capable of reducing the ferricytochrome with a halftime of 1-2 ms under optimal conditions, has an oxidation-reduction midpoint potential of close to 150 mV at pH 7.0, and apparently requires two electrons and two protons for its equilibrium reduction. The state of reduction of Z, which may be a quinone.protein complex near the inner (cytochrome c2) side of the membrane, appears to govern the rate at which the cyclic photosynthetic electron transport system can operate. If Z is oxidized prior to the flash-oxidation of cytochrome c2, the re-reduction of the cytochrome takes hundreds of milliseconds and no third phase of the carotenoid bandshift occurs. In contrast if Z is reduced before flash activation, the cytochrome is rereduced within milliseconds and the third phase of the carotenoid bandshift occurs. The prior reduction of Z also has a dramatic effect on the uncoupler sensitivity of the rate of electron flow; if it is oxidized prior to activation, uncoupler can stimulate the cytochrome rereduction after several turnovers by less than tenfold, but if it is reduced prior to activation, the stimulation after several turnovers can be as dramatic as a thousandfold. The results suggest that Z plays a central role in controlling electron and proton movements in the ubiquinone cytochrome b-c2 oxido-reductase.

Bacterial Chromatophores↗
PubMed1975

Functional organization of mitotic microtubules. Physical chemistry of the in vivo equilibrium system.

Equilibrium between mitotic microtubules and tubulin is analyzed, using birefringence of mitotic spindle to measure microtubule concentration in vivo. A newly designed temperature-controlled slide and miniature, thermostated hydrostatic pressure chamber permit rapid alteration of temperature and of pressure. Stress birefringence of the windows is minimized, and a system for rapid recording of compensation is incorporated, so that birefringence can be measured to 0.1 nm retardation every few seconds. Both temperature and pressure data yield thermodynamic values (delta H similar to 35 kcal/mol, delta S similar to 120 entropy units [eu], delta V similar to 400 ml/mol of subunit polymerized) consistent with the explanation that polymerization of tubulin is entropy driven and mediated by hydrophobic interactions. Kinetic data suggest pseudo-zero-order polymerization and depolymerization following rapid temperature shifts, and a pseudo-first-order depolymerization during anaphase at constant temperature. The equilibrium properties of the in vivo mitotic microtubules are compared with properties of isolated brain tubules.

Animals↗