Biomedical subjects
Publications and source records attributed to F R Quinn.
While the potential for curative treatment of atrial fibrillation has generated much interest in the role of catheter ablation, its widespread use has been limited by a number of factors.
Na+-Ca2+ exchanger (NCX) protein levels and activity were measured in myocardium from the basal region of the left ventricle of rabbit hearts with significant left ventricular dysfunction (LVD), 8-9 weeks after an apical infarction. NCX protein abundance was higher in the tissue homogenates (121 +/- 11%) and purified membrane fractions (143 +/- 12%) in the LVD compared to the sham-operated (sham) group. NCX mRNA was also higher in the LVD group (126%). Lower NCX protein expression was observed in the membrane fractions from the epicardium compared to the endocardium in both the sham and LVD groups. Transmembrane currents were recorded in isolated cardiomyocytes by single-electrode voltage clamp; [Ca2+]i was measured using Fura-2. Rapid application of 10 mmol l-1 caffeine was used to induce Ca2+ release from the sarcoplasmic reticulum. The subsequent NCX-mediated Ca2+ efflux rate constant was lower (70% of sham) in the LVD group. NCX currents were measured in cardiomyocytes dialysed with 250 nM Ca2+ (50 mmol l-1 EGTA). A lower NCX current (75% of sham) was observed in the LVD group. Lower NCX activity was also observed in cardiomyocytes isolated from the epicardium compared to the endocardium; a transmural difference that was also seen in the LVD group. Reduced activity despite increased protein expression may result from reduced Ca2+ sensitivity of the allosteric regulation of NCX. However, measurements indicated increased Ca2+ sensitivity in the LVD group. Cardiomyocytes from LVD hearts displayed a marked reduction in the transverse tubule area (59% of sham) and the surface area/volume ratio (80% of sham). Disrupted transverse tubule structure may contribute to the decrease in NCX activity despite increased protein expression in LVD.
Calcium (Ca(2+)) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca(2+) is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca(2+) store. These fluxes occur by the transient activity of Ca(2+)-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca(2+)-handling proteins, in particular the SR Ca(2+)-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca(2+) available for contraction. In the steady state, the Ca(2+)-content of the SR is essentially a balance between Ca(2+)-uptake via SERCA2a pump and Ca(2+)-release via the cardiac SR Ca(2+)-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca(2+) content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca(2+)-uptake, and (ii) reduction of SR Ca(2+)-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and/or Ca(2+)-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca(2+)-leak. Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMP-levels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca(2+)-cycling proteins may have the potential to fill this gap.
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Terephthalamidine (NSC 57155) is one of 800 terephthalanilides and related compounds which were synthesized and tested preclinically in the late 1950's and early 1960's. Based upon their activity against murine leukemias, some of these agents were tested briefly in clinical trials at that time. Despite the observation of responses, the compounds were dropped because of severe and unusual neurotoxicity. More recently, terephthalamidine has been screened for antitumor activity and chosen for further clinical investigation by the NCI's Project for the Review of Old Drugs (P.R.O.D.) because of its novel structure and spectrum of preclinical activity. The current availability of a plasma assay for the drug permits further study of its clinical pharmacokinetics and pharmacodynamics and, perhaps, the development of improved scheduling strategies.
2',3'-Dideoxyadenosine, C10H13N5O2, Mr = 235.24, orthorhombic, P2(1)2(1)2(1), a = 7.7404(4), b = 9.9843(9), c = 14.0842(10) A, V = 1088.46 A3, Z = 4, Dx = 1.435 Mg m-3, lambda(CuK alpha) = 1.5418 A, mu = 0.8326 mm-1, F(000) = 496, T = 296 K, final R = 0.032 for 1088 observed reflections. 2',3'-Dideoxycytidine, C9H13N3O3, Mr = 211.21, tetragonal, P4(1)2(1)2, a = 8.6802(4), c = 26.1386(14) A, V = 1969.44 A3, Z = 8, Dx = 1.424 Mg m-3, lambda(CuKa) = 1.5418 A, mu = 0.8701 mm-1, F(000) = 896, T = 296 K, final R = 0.050 for 1116 observed reflections. In both compounds the sugar rings have conformations intermediate between envelope and half chair but somewhat different pseudorotations. The relative orientations of the sugar and base are different in the two molecules with dideoxyadenosine being at the boundary of syn and anti and deoxycytidine being anti.
Desulfurization of thiocolchicine with Raney nickel in a hydrogen atmosphere yielded tetrahydromethoxycolchicine (2), which was readily separated from unreacted thiocolchicine by chromatography and was smoothly oxidized to 10-demethoxycolchicine (colchicide) by Pd/C in refluxing toluene. Several analogues of colchicide were prepared from the corresponding thiocolchicines by this procedure. Treatment of colchicide with concentrated sulfuric acid yielded 2-demethylcolchicide. Colchicide and its analogues were found to be inactive in a tubulin-binding assay. Evidence is presented that colchicide prepared earlier from thiocolchicine with Raney nicel in aerial atmosphere was contamination with 1-2% thiocolchicine.
A recent study published by the National Academy of Sciences emphasized an acute shortage of data on the toxic effects of chemicals in man and animals. This shortage makes risk assessment difficult and impacts seriously on the development of a sound environmental policy. The National Cancer Institute, in its search for effective anti-cancer agents, has determined quantitative as well as qualitative toxicities for a large number of chemicals. Probit analysis was used to derive lethalities (LD50s) from data obtained in the process of testing anti-cancer agents in mice. These data were compared with those derived from testing those same agents in normal mice and it was found that a correlation exists between the two toxicities. Toxicities derived from NCI testing in normal animals were compared with published values and a similar correlation was found. LD50s were derived for all compounds tested in normal mice as well as those tested in mice bearing L1210 and P388 lymphocytic leukemias. Over 32,000 LD50s were derived for 22,597 unique compounds.
Novel and known analogues of thiocolchicine were evaluated in vitro in a tubulin binding assay and in vivo in mice for acute toxicity and in the P388 lymphocytic leukemia assay. This evaluation included N-acyldeacetylthiocolchicines, N-(alkoxycarbonyl)deacetylthiocolchicines, thiodemecolcine and its methyl carbamate, and O-ethyl ethers of demethylthiocolchicines. Selective ether cleavage of thiodemecolcine with concentrated sulfuric acid at 50 degree C afforded the 2-demethyl congener, characterized as its N,O-diacetyl derivative. Several of the compounds showed high potency in the tubulin binding assay, matching the potency of colchicine. Several N-(alkoxycarbonyl)deacetylcolchicines (carbamates) exhibited strong binding affinity to tubulin but had only weak activities against the P388 tumor system, suggesting that other factors besides tubulin binding may be important for the biological effects. The compounds potent in the tubulin binding assay and in the P388 leukemia assay in mice were generally also toxic to mice in the acute toxicity test, showing thus a similar behavior of thiocolchicines to that observed earlier with colchicines. A considerable amount of data collected for 2-demethyl- and 3-demethylthiocolchicine suggests that the latter represents a broad-spectrum antitumor agent of considerable promise and possibly a less toxic substitute for colchicine.
Quantitative structure-activity relationships (QSAR) were derived for a number of 2,6-mono- and disubstituted purines. The derived equations relate the anticancer activity in murine Adenocarcinoma CA755 to the molar refractivity of substituents at position 2 and electron-withdrawing effects of substituents at position 6. A QSAR was also derived for the acute toxicity (LD50) of substituents at position 6. The results suggest that toxicity is relatively independent of the nature of the substituent.
Quantitative structure-activity relationships (QSAR) are developed for the acute toxicity of a number of rifamycin B amides and hydrazides in mice. The equations indicate a parabolic dependence of toxicity on the partition coefficient. Two related compounds, rifamycin SV and rifamycin B, were included with the amides in a more general correlation. The latter equation was used to predict the toxicity of rifampicin, suggesting that this relationship may be of general use for the prediction of rifamycin toxicity.
Linear free energy relationships were derived for several monosubstituted purines. The derived equations relate to the pKa to the Hammett constants sigma m and sigma p. A general linear free energy relationship was derived that permits calculation of the pKa of polysubstituted purines. The results suggest that correlation of biological data with standard parameters is feasible.
A quantitative structure-activity relationship (QSAR) was derived for colchicine and 14 analogues acting against P388 lymphocytic leukemia in mice. Twelve additional compounds were synthesized to reinforce and confirm the correlation. The final correlation indicates that there is a parabolic dependence of antitumor potency on the partition coefficient with log P0=1.17. When an amino nitrogen is present on the B ring, increased potency is favored by acylation of the nitrogen. The most potent compound of the series was the 7-fluoroacetamide analogue. Strong electron-withdrawing groups substituted at the 10 position of the tropolone ring destroy activity. Electron-releasing groups at position 10 improve potency slightly but have a limited effect.
A method for extracting LD50 values from antitumor test data is described. A quantitative structure--activity relationship (QSAR) for 7- and 10-substituted colchicines is presented. This correlation equation closely parallels that which had been derived earlier for potency. This result indicates that attempts to modify 7- and 10-substituted colchicines in order to decrease toxicity will likely produce a simultaneous decrease in potency. Ring A modified colchicines do not obey the potency and toxicity correlations. 4-Substituted colchicines appear promising in terms of decreased toxicity, greater ILS, and a broader therapeutic range.
Twenty-two 3-substituted rifamycins were tested for inhibition of mammalian alpha and beta DNA polymerase and viral RNA-dependent DNA polymerase ("reverse transcriptase"). Quantitative structure--activity relationships (QSAR) were formulated for the three systems. Inhibition is linearly dependent on the partition coefficient and is highly favored by the presence of bulky hydrazones or oximes. None of these agents proved to be a selective or specific inhibitor of reverse transcriptase. A correlation in terms of log P and (log P)2 was obtained from data on a more closely related set of analogues from a published study. For murine reverse transcriptase, log P0 = 5.1.
Quantitative structure-activity relationships (QSAR) are developed for both the antitumor activity (B-16 melanoma) and cardiotoxicity of a set of anthracycline derivatives, for the purposes of finding exploitable differences between the two which would lead to improvements in the therapeutic indices of these compounds. It was found that most structural features which lead to improvement in antitumor activity, such as increases in drug hydrophilicity, also lead to increases in cardiotoxicity. However, demethoxylation and demethoxylation at the 4-position of these molecules appears to have much greater effect on cardiotoxicity than on antitumor activity. If these effects are brought about by alterations in the oxidation-reduction potential of the quinone structure, as is suggested, then it may be possible to make analogs with a better therapeutic index by the introduction of small hydrophilic electron-releasing groups in the A-ring of these adriamycin derivatives that are conjugated with the carbonyl functions.
Quantitative structure-activity relationships (QSAR) have been formulated for phenyl-, pyrazolyl-, and imidazolyltriazenes acting L1210 leukemia in mice. All three sets of congeners have the same ideal lipophilicity (log Po approximately 1). Electron releasing substituents increase potency; ortho substitution decreases activity. The synthesis of a number of new triazenes and some of their partition coefficients are reported.