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Biomedical subjects

S C Kuo

Publications and source records attributed to S C Kuo.

At least 91 records · Page 5Linked to original sources
PubMed1994

Antitumor agents. 150. 2',3',4',5',5,6,7-substituted 2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.

As part of our continuing search for potential anticancer drug candidates in the 2-phenyl-4-quinolone series, we have synthesized a series of 6,7-methylenedioxy-substituted and unsubstituted 2-phenyl-4-quinolones, as well as related compounds. Their in vitro inhibition of human tumor cell lines and tubulin polymerization is reported. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization. Compounds 7, 9, 13, 16, 22, 23, 36, and 37 showed potent inhibitory effects in both assays. All rigid analogs (47-49) and trimethoxy-substituted compounds showed little or no activity. Substitution at the 4'-position also resulted in compounds with little or no activity, except for hydroxyl or methyl groups at this position. Further investigation is underway to determine if substitution at the 3'-position will result in compounds with increased activity.

Animals↗
PubMed1994

Suppressive effect of 2-phenyl-4-quinolone (YT-1) on hind-paw edema and cutaneous vascular plasma extravasation in mice.

Like indomethacin, BW755C, diphenhydramine and methysergide, 2-phenyl-4-quinolone (YT-1) suppressed the polymyxin B-induced hind-paw edema. This inhibitory effect of YT-1 was also demonstrated in adrenalectomized mice. YT-1 inhibited the antidromic stimulation of saphenous nerve-induced plasma leakage in dorsal paw skin and reduced the volume of plasma exudation in PCA reaction. Bradykinin-, substance P- and compound 48/80-induced mouse ear edema was suppressed by YT-1 in a dose-dependent manner. In isolated rat peritoneal mast cells, YT-1 produced a dose-dependent inhibition of bradykinin-, substance P- and compound 48/80-induced histamine and beta-glucuronidase release. YT-1 also reduced the TXB2 formation from PMN leukocytes with IC50 2.0 +/- 0.5 microM, however with little effect on LTB4 formation. Histamine- and serotonin-induced plasma exudation in ear edema were reduced by YT-1. Moreover, the maximal response of ileum contraction caused by histamine and serotonin were also suppressed by YT-1 in a dose-dependent manner. In compound 48/80-pretreatment mice, YT-1 failed to suppress the bradykinin- and substance P-induced ear edema to a significantly greater extent than diphenhydramine combined with methysergide did. These results indicate that the inhibitory effect of YT-1 on local edema formation is not through the release of steroid hormones from adrenal gland, and is probably by suppressing the release of chemical mediators from mast cells, inhibition of prostaglandins formation, and noncompetitive but selective protection of the vasculature against the histamine- and serotonin-induced plasma extravasation.

Animals↗
PubMed1994

Synthesis and antiallergic activities of 2-alkyl-3,4-dimethylfuro[2,3-c] pyrazole-5-carboxamides and related compounds.

A series of 2-substituted 3,4-dimethylfuro[2,3-c]pyrazole- 5-carboxamides and related compounds have been synthesized and their antiallergic activities were evaluated. Most derivatives with a lower alkyl group at position 2 were orally active. Among them, N-ethyl-2,3,4-trimethylfuro[2,3-c]pyrazole- 5-carboxamide (III3),2-ethyl-N-methyl-3,4-dimethylfuro[2,3-c]pyrazole-5-ca rboxamide (III14), 2-isopropyl-N-methyl-3,4-dimethylfuro[2,3-c]pyrazole-5- carboxamide (III27),5-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-2,3,4- trimethylfuro [2,3-c]pyrazole (IV1) and 5-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-2-isopropyl-3,4- dimethylfuro[2,3-c]pyrazole (IV3) showed promising antiallergic effects. The structure-activity relation of these 3,4-dimethylfuro[2,3-c] pyrazole derivatives was examined. An amide or 5-oxo-1,3,4-oxadiazole substituent at position 5 was favorable, while introduction of a carboxylic acid or acrylic acid moiety was unfavorable. However, none of these compounds exerted a significant inhibitory effect on mast cell degranulation. Compound III27 and IV3 showed potent anti-allergic activity. We found that they also suppressed histamine-, serotonin-, bradykinin- and substance P-induced ear edema in mice. In compound 48/80-pretreated mice, the preformed mediators in mast cells in the ear were greatly reduced. Under this condition, the bradykinin- and substance P-induced ear edema was suppressed by compound III27 and IV3 to a significantly greater extent than by diphenhydramine combined with methylsergide. These results indicated that the antiallergic effect of 3,4-dimethylfuro[2,3-c]pyrazole derivatives probably involves protection of the vasculature against the effects of challenge by several mediators.

Animals↗
PubMed1993

Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin.

A series of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds have been synthesized and evaluated as cytotoxic compounds and as antimitotic agents interacting with tubulin. The 2-phenyl-4-quinolones (22-30) with substituents (e.g. F, Cl, and OCH3) at C-6, C-7, and C-8 show, in general, potent cytotoxicity against human lung carcinoma (A-549), ileocecal carcinoma (HCT-8), melanoma (RPMI-7951), and epidermoid carcinoma of the nasopharynx (KB) and two murine leukemia lines (P-388 and L1210). Introduction of alkyl groups at N-1 or C-4 oxygen led to inactive compounds (35-43 and 50). In addition, compounds 24, 26, and 27 were evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. These compounds demonstrated the most marked effects in the screen on two colon carcinoma cell lines (COLO-205 and KM-20L2) and on a central nervous system tumor cell line (SF-539) with compound 26 the most potent of the three agents. Compounds 24, 26, and 27 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. The three agents also inhibited the binding of radiolabeled colchicine to tubulin, but this inhibition was less potent than that obtained with the natural products.

Animals↗
PubMed1993

Force of single kinesin molecules measured with optical tweezers.

Isometric forces generated by single molecules of the mechanochemical enzyme kinesin were measured with a laser-induced, single-beam optical gradient trap, also known as optical tweezers. For the microspheres used in this study, the optical tweezers was spring-like for a radius of 100 nanometers and had a maximum force region at a radius of approximately 150 nanometers. With the use of biotinylated microtubules and special streptavidin-coated latex microspheres as handles, microtubule translocation by single squid kinesin molecules was reversibly stalled. The stalled microtubules escaped optical trapping forces of 1.9 +/- 0.4 piconewtons. The ability to measure force parameters of single macromolecules now allows direct testing of molecular models for contractility.

Adenosine Triphosphate↗
PubMed1993

Physicochemical characterization of 9,10-anthraquinone 2-carboxylic acid.

The physicochemical properties of 9,10-anthraquinone-2-carboxylic acid (AQCA) were investigated by thermal analysis, powder X-ray diffraction pattern, solubility, and partition coefficient. The chemical structure of AQCA was confirmed by the data from UV, Fourier transform IR (FTIR), and NMR analyses. Solubility and partition coefficient data were pH dependent. A new methanolic solvate of AQCA that lost 9.34% of its initial weight from 70 to 100 degrees C was found by thermogravimetric analysis. Sublimation of AQCA occurred at temperatures > 250 degrees C and needle-like crystals (Form I) were formed. The water solubility of AQCA increased with temperature; its heat of solution was 32.7 kJ/mol. A differential scanning calorimetry-FTIR microscopic system correlated a thermal phase transition with structural changes due to loss of methanol from the solvate, and three-dimensional FTIR spectra indicated that the process was complete by 100 degrees C. The kinetics of desolvation and sublimation from each crystal form of AQCA were determined. The activation energy of desolvation of methanol from solvate was 425.8 kJ/mol, and the activation energy of sublimation from Form I or desolvated crystals was 182.7 kJ/mol.

Anthraquinones↗
PubMed1993

Heterogeneity and probabilistic binding contributions to receptor-mediated cell detachment kinetics.

Biospecific cell adhesion is mediated by receptor-ligand bonds. Early theoretical work presented a deterministic analysis of receptor-mediated cell attachment and detachment for a homogeneous cell population. However, initial comparison of a deterministic framework to experimental detachment profiles of model "cells" (antibody-coated latex beads) did not show qualitative or quantitative agreement (Cozens-Roberts, C., D.A. Lauffenburger, and J.A. Quinn. 1990. Biophys. J. 58:857-872). Hence, we determine the contributions of population heterogeneity and probabilistic binding to the detachment behavior of this experimental system which was designed to minimize experimental and theoretical complications. This work also corrects an error in the numerical solution of the probabilistic model of receptor-mediated cell attachment and detachment developed previously (Cozens-Roberts, C., D.A. Lauffenburger, and J.A. Quinn. 1990. Biophys J. 58:841-856). Measurement of the population distribution of the number of receptors per bead has enabled us to explicitly consider the effect of receptor number heterogeneity within the cell-surface contact area. A deterministic framework that incorporates receptor number heterogeneity qualitatively and quantitatively accounts in large part for the model cell detachment data. Using measured and estimated parameter values for the model cell system, we estimate that about 90% of the observed kinetic detachment behavior originates from heterogeneity effects, while about 10% is due to probabilistic binding effects. In general, these relative contributions may differ for other systems.

Biophysical Phenomena↗
PubMed1993

Relationship between receptor/ligand binding affinity and adhesion strength.

Receptor-mediated cell adhesion is a central phenomenon in many physiological and biotechnological processes. Mechanical strength of adhesion is generally presumed to be related to chemical affinity of receptor/ligand bonds, but no experimental study has been previously directed toward this issue. Here we investigate the dependence of receptor/ligand adhesion strength on bond affinity using a radial fluid flow chamber assay to measure the force needed to detach polystyrene beads covalently coated with immunoglobulin G from glass surfaces covalently coated with protein A. A spectrum of animal species sources for immunoglobulin G permits examination of three decades of protein A/immunoglobulin G binding affinity. Our results for this model system demonstrate that adhesion strength varies with the logarithm of the binding affinity, consistent with a prediction from the theoretical model by Dembo et al. (Dembo, M., D.C. Torney, K. Saxman, and D. Hammer. 1988. Proc. R. Soc. Lond. Ser. B 234:55-83).

Animals↗
PubMed1993

Inhibition of platelet aggregation by shikonin derivatives isolated from Arnebia euchroma.

Four antiplatelet components were isolated from Arnebia euchroma. They inhibited the aggregation of washed rabbit platelets caused by collagen, arachidonic acid, platelet-activating factor, ADP, or thrombin. The potency of inhibiting collagen-induced platelet aggregation is in the following order: acetylshikonin (IC50 = 2.1 microM), teracrylshikonin (2.8 microM), beta, beta-dimethylacrylshikonin (4.2 microM), and shikonin (10.7 microM). In rat aorta, acetylshikonin and shikonin inhibited high potassium and norepinephrine-induced contractions, while beta, beta-dimethylacrylshikonin and teracrylshikonin potentiated the phasic contraction caused by norepinephrine.

Animals↗
PubMed1993

Mechanical and electrophysiological studies on the positive inotropic effect of 2-phenyl-4-oxo-hydroquinoline in rat cardiac tissues.

1. The pharmacological and electrophysiological effect of 2-phenyl-4-oxo-hydroquinoline (YT-1), a new synthetic agent, were determined in rat isolated cardiac tissues and ventricular myocytes. 2. YT-1 was found to have a positive inotropic effect in both atria and ventricular muscles but did not cause significant increases in the spontaneously beating rate of right atria. 3. The positive inotropic effect of YT-1 was antagonized neither by beta-nor by alpha-adrenoceptor antagonists but was partially antagonized by a Ca2+ channel blocker (verapamil) and a K+ channel blocker (4-AP). 4. The action potential duration and amplitude of ventricular cells were progressively increased as the concentration of YT-1 was increased from 3 to 30 microM. 5. A voltage clamp study revealed that the prolongation of action potential duration by YT-1 was associated with a prominent inhibition of 4-AP-sensitive transient outward current (I(to)). At potentials negative to the reversal potential of K1-channels, the inward current through these channels was partially reduced by YT-1. At potentials positive to the reversal potential, the outward current through these channels was affected very little. 6. Although YT-1 blocked the amplitude of I(to), the voltage-dependence of the steady-state inactivation of I(to), was unaffected. 7. Apart from the inhibition of K+ currents, YT-1 also inhibited the sodium inward current. 8. The evidence suggests that YT-1 increases the slow inward Ca2+ current (ICa) significantly. 9. It is concluded that the positive inotropic effect of YT-1 is due predominantly to the increase of ICa and inhibition of I(to).

Action Potentials↗
PubMed1992

HA-29: an inhibitor of thromboxane A2 formation with antagonism of thromboxane A2/prostaglandin endoperoxide receptor in rabbit platelets.

HA-29, 2-[(3-methoxyphenyl)methyl]-pyrano[2,3-c]pyrazol-6(1H)-one, was investigated for its inhibitory mechanism of action in washed rabbit platelets. This compound inhibited the aggregation and ATP release of rabbit platelets induced by arachidonic acid and collagen in a concentration-dependent manner, without affecting those induced by ADP, PAF and thrombin. Prolongation of the incubation time of HA-29 with platelets did not cause further inhibition and the aggregability of the agent-treated platelets could be restored after washing of platelets. The concentration-response curve of U-46619-induced platelet aggregation was shifted to the right by HA-29 in a concentration-dependent manner, but the maximal aggregation was suppressed by HA-29. The pA2 and pA10 values of HA-29 on U-46619-induced platelet aggregation were 4.26 and 3.58, respectively, with a slope value of -1.4. The U-46619-induced aggregation was markedly disaggregated by HA-29 even it was added 5 min after U-46619. HA-29 inhibited the secondary aggregation and ATP release, but not the primary aggregation of human platelet-rich plasma induced by ADP and epinephrine. Thromboxane B2 formation caused by arachidonic acid, collagen and thrombin was markedly suppressed by HA-29. HA-29 also inhibited the formation of prostaglandin D2 caused by arachidonic acid. HA-29 inhibited almost completely the formation of inositol monophosphate caused by U-46619, but not that by collagen or thrombin. HA-29 did not affect U-46619-induced contraction of rat aorta. It is concluded that the antiplatelet effect of HA-29 is due to the inhibition of thromboxane A2 formation and blockade of thromboxane A2/prostaglandin endoperoxide receptor.

Adenosine Triphosphate↗
PubMed1992

Vasorelaxation of rat thoracic aorta caused by two Ca(2+)-channel blockers, HA-22 and HA-23.

The pharmacological effects of HA-22 (2-(4'methoxyphenylmethyl)-3,4-dimethylpyrano[2,3-c]pyrazol- 6(2H)-one) and HA-23 (2-(2'-thienylmethyl)-3,4-dimethylpyrano[2,3-c]pyrazol-6(2H) -one) on rat isolated thoracic aorta have been examined. In high potassium medium (60 mM), Ca2+ (0.03-3 mM)-induced vasoconstriction was inhibited by HA-22 and HA-23 (10-100 micrograms mL-1). Cromakalim-relaxed aortic rings precontracted with 15 mM but not 60 mM K+. However, HA-22, HA-23 and verapamil produced a greater relaxation in 60 mM than in 15 mM K(+)-induced contraction. The tonic contractions elicited by KCl (60 mM) and Bay K 8644 (10(-7)M) were also relaxed by the addition of HA-22 and HA-23. The phenylephrine concentration-response curves displayed antagonism by HA-22 and HA-23 (10-100 micrograms mL-1) in a non-competitive manner. The caffeine (10 mM)-induced contraction and cAMP or cGMP levels were not affected by HA-22 or HA-23. It is concluded that HA-22 and HA-23 relaxed the rat aorta by suppressing the Ca2+ influx through both voltage-dependent and receptor-operated Ca2+ channels.

Animals↗
PubMed1992

Synthesis and antiplatelet activities of N-arylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives.

A series of new 1- and 2-arylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives were synthesized and examined for their antiplatelet activities. Some of these compounds showed significant inhibitory activities. Among them, 1-phenylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6(1H)-one (4a), 2-(2'-methoxyphenyl)methyl-3,4-dimethylpyrano[2,3-c]pyrazol-6(2H)- one (3e) and 2-(3'-methoxyphenyl)methyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-(2H) - one (3f) were the most effective. These inhibitors acted in a concentration-dependent manner. The antiplatelet effect of compound 3f is due to the inhibition of thromboxane A2 formation and the blockade of thromboxane A2/prostaglandin endoperoxide receptor in washed rabbit platelets.

Animals↗
PubMed1991

Lateral movements of membrane glycoproteins restricted by dynamic cytoplasmic barriers.

Cell membranes often are patchy, composed of lateral domains. These domains may be formed by barriers within or on either side of the membrane bilayer. Major histocompatibility complex (MHC) class 1 molecules that were either transmembrane- (H-2Db) or glycosylphosphatidylinositol (GPI)-anchored (Qa2) were labeled with antibody-coated gold particles and moved across the cell surface with a laser optical tweezers until they encountered a barrier, the barrier-free path length (BFP). At room temperature, the BFPs of Qa2 and H-2Db were 1.7 +/- 0.2 and 0.6 +/- 0.1 (micrometers +/- SEM), respectively. Barriers persisted at 34 degrees C, although the BFP for both MHC molecules was fivefold greater at 34 degrees C than at 23 degrees C. This indicates that barriers to lateral movement are primarily on the cytoplasmic half of the membrane and are dynamic.

Animals↗
PubMed1991

6-Pentadecylsalicylic acid: an antithrombin component isolated from the stem of Rhus semialata var. roxburghii.

Bioassay-directed fractionation of the n-hexane extract of the stem of Rhus semialata Murr. var. roxburghii DC (Anacardiaceae) has led to the isolation of 6-pentadecylsalicylic acid. It showed antithrombin activity at 50 micrograms/ml in the amidolytic method. It also prolonged the clotting time in a dose-dependent manner in the clotting assay of thrombin-fibrinogen interaction.

Amino Acid Sequence↗