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S C Kuo

Publications and source records attributed to S C Kuo.

At least 55 records · Page 3Linked to original sources
PubMed1998

Three new flavonoids and antiallergic, anti-inflammatory constituents from the heartwood of Dalbergia odorifera.

Three new flavonoids, (3R)-4'-methoxy-2',3,7-trihydroxyisoflavanone (11), 7-methoxy-3,3',4',6-tetrahydroxyflavone (18), and 2',7-dihydroxy-4',5'-dimethoxyisoflavone (22), were isolated from the heartwood of Dalbergia odorifera T. Chen. (Leguminosae), together with twenty-two known compounds, (S)-4-methoxydalbergione (1), cearoin (2), medicarpin (3), formononetin (4), sativanone (5), 3-hydroxy-9-methoxy-coumestan (6), meliotocarpan A (7), isoliquiritigenin (8), stevein (9), liquiritigenin (10), 3',4',7-trihydroxyflavanone (12), butein (13), 3'-hydroxymelanettin (14), koparin (15), bowdichione (16), fisetin (17), melanettin (19), sulfuretin (20), 3'-hydroxydaidzein (21), 3'-O-methylviolanone (23), xenognosin B (24), and dalbergin (25). These flavonoids were evaluated in antiallergic and anti-inflammatory tests. The results showed that (S)-4-methoxydalbergione (1) and cearoin (2) exhibited antiallergic activity while (S)-4-methoxydalbergione (1), cearoin (2), butein (13), koparin (15), bowdichione (16), 3'-O-methylviolanone (23), and xenognosin B (24) showed significant anti-inflammatory activity.

Animals↗
PubMed1998

Effect of PP1D-1, a synthetic antiplatelet compound, on rabbit platelets.

The antiplatelet mechanism of a synthetic compound, 2-chloro-3-methoxycarbonylpropionamido-1,4-naphthoquinone (PP1D-1), was studied by employing washed rabbit platelets in vitro. PP1D-1 concentration-dependently inhibited thrombin (0.1 U/ml)-, platelet-activating factor (2 ng/ml)-, collagen (10 microg/ml)-, arachidonic acid (100 microM)- and U46619 (1 microM)-induced aggregation and ATP release in washed rabbit platelets. The IC50 values of PP1D-1 for aggregation induced by the above inducers are 17.9+/-1.7, 9.8+/-1.1, 3.9+/-0.4, 1.8+/-0.3 and 1.7+/-0.3 microM, respectively. PP1D-1 did not affect platelet thromboxane B2 or prostaglandin D2 formation induced by arachidonic acid, indicating that it did not affect cyclooxygenase and thromboxane synthase activities. PP1D-1 significantly inhibited the formation of inositol 1,4,5-trisphosphate caused by these five platelet stimulators. Moreover, PP1D-1 inhibited the increase in intracellular calcium concentration induced by these agents. On the contrary, PP1D-1 did not inhibit thapsigargin-elevated intracellular calcium concentration in indomethacin-pretreated platelets, indicating it did not influence the effect of thapsigargin. According to these data, PP1D-1 exerts antiplatelet effects mainly by inhibiting phosphoinositide turnover.

Adenosine Triphosphate↗
PubMed1997

Inhibition of nitric oxide synthase expression by PPM-18, a novel anti-inflammatory agent, in vitro and in vivo.

We studied the effect of PPM-18, a chemically synthesized naphthoquinone derivative and also an anti-inflammatory agent, on the lipopolysaccharide (LPS)-activated inducible NO synthase (iNOS) expression in rat alveolar macrophages. Pretreatment of macrophages with PPM-18 (0.1-10 microM) significantly inhibited nitrite production, iNOS protein expression and iNOS mRNA accumulation. PPM-18 did not directly affect the enzymic activities of iNOS and other constitutive NOS forms. The LPS-induced increase in nuclear transcription factor kappaB (NF-kappaB) p65 and p50 in nucleus was suppressed by PPM-18 (10 microM). Moreover electrophoretic mobility-shift assays demonstrated that PPM-18 inhibited DNA binding to NF-kappaB induced by LPS in whole cells but not when added in the nuclear extract, suggesting that PPM-18 did not interfere directly with the binding of NF-kappaB to DNA and that some events had to be processed before NF-kappaB could bind DNA. Examination of NF-kappaB showed that PPM-18 stabilized the NF-kappaB inhibitor, IkappaBalpha, by preventing its degradation from NF-kappaB. Therefore the stabilization of IkappaBalpha might have contributed to the inhibition of NF-kappaB activation. These results also indicate strongly that NF-kappaB is involved in the production of NO on stimulation by LPS. PPM-18 significantly decreased the production of tumour necrosis factor alpha in response to LPS. PPM-18 protects mice against LPS-induced lethal toxicity. These results also indicate that PPM-18 is a potent inhibitor of iNOS expression by blocking the binding of NF-kappaB to promoter and exerts a beneficial effect in the mouse model of sepsis.

Animals↗
PubMed1997

Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization.

As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different selectivity for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.

Antineoplastic Agents↗
PubMed1997

Antitumor agents. 174. 2',3',4',5,6,7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.

Two series of 2',3',4',5,6,7-substituted 2-phenyl-1,8-naphthyridin-4-ones and 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones have been synthesized and evaluated as cytotoxic compounds and as inhibitors of tubulin polymerization. Most 2-phenyl-1,8-naphthyridin-4-ones showed potent cytotoxic and antitubulin activities, whereas 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones showed no activity in either assay. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization in the 2-phenyl-1,8-naphthyridin-4-one series. The 2-phenyl-1,8-naphthyridin-4-ones (44-49) with a methoxy group at the 3'-position showed potent cytotoxicity against most tumor cell lines with GI50 values in the low micromolar to nanomolar concentration range in the National Cancer Institute's 60 human tumor cell line in vitro screen. Introduction of substituents (e.g. F, Cl, CH3, and OCH3) at the 4'-position led to compounds with reduced or little activity and substitution at the 2'-position resulted in inactive compounds. The effects of various A-ring substitutions on activity depend on the substitution in ring C. Compounds 44-50 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Compounds 44-49 also inhibited the binding of radiolabeled colchicine to tubulin, but the inhibition was less potent than that obtained with the natural products. Further investigation is underway to determine if substitution at the 3'-position and multisubstitutions in ring C will result in compounds with increased activity.

Animals↗
PubMed1997

Impairment of phosphatidylinositol signaling in acetylshikonin-treated neutrophils.

In rat neutrophils, formylmethionyl-leucyl-phenylalanine (fMLP)-induced inositol phosphate formation was concentration-dependently inhibited by acetylshikonin as well as by a putative phospholipase C (PLC) inhibitor [6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-p yrrole-2,5-dione (U73122). The IC50 value of acetylshikonin for the inhibition of inositol trisphosphate (IP3) formation was estimated to be 16.1 +/- 1.5 microM. The reduction of inositol phosphate levels appeared to reflect inhibition of PLC activity because the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) catalyzed by a soluble fraction from neutrophils was also inhibited by acetylshikonin (IC50 value 21.4 +/- 6.1 microM) over the same range of concentrations. Although acetylshikonin alone evoked Ca2+ and Mn2+ influx into neutrophils in Ca2+-containing medium, acetylshikonin, like U73122, inhibited Ca2+ release (IC50 value approximately 5.3 +/- 0.4 microM) from internal stores in Ca2+-free medium. These results indicate that acetylshikonin inhibits phosphatidylinositol signaling in neutrophils.

Animals↗
PubMed1997

YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice.

YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole), a nitric oxide (NO)-independent activator of soluble guanylate cyclase, has been shown to inhibit platelet activation and aggregation in vitro through the generation of cGMP. In the present study, we assessed the antithrombotic effect of YC-1 in models of experimental thrombosis in mice. YC-1 (10, 30 micrograms/g, i.p.)-treated mice showed a prolonged tail bleeding time 30 min after injection (from control 91.0 +/- 6.4 s to 208.6 +/- 22.7 s and 291.8 +/- 42.4 s, respectively). In contrast, aspirin at a dose of 30 micrograms/g (i.p.) prolonged the bleeding time to more than 600 s. Platelet-rich thrombus formation was induced by irradiation of the mesenteric venule with filtered light in mice pretreated intravenously with fluorescein sodium. YC-1 (30 micrograms/g, i.p.) markedly prolonged the occlusion time of irradiated venules (from control 146.1 +/- 19.0 s to 275.6 +/- 24.5 s) in heparinized (1 U/g) mice. In the same condition, aspirin (100 micrograms/g) only slightly prolonged the time required for occlusion (193.2 +/- 13.2 s). In a model of fatal pulmonary thromboembolism induced by intravenous injection of ADP (300 micrograms/g), YC-1 was effective in reducing mortality when administered intraperitoneally at doses of 10-30 micrograms/g. The antithrombotic effect of YC-1 was correlated with the inhibition of ADP-induced platelet aggregation ex vivo. In contrast, aspirin (30, 100 micrograms/g) did not inhibit ADP-induced pulmonary thromboembolism in vivo or platelet aggregation ex vivo. YC-1 (3, 10 micrograms/g) also exhibited profibrinolytic activity ex vivo, as revealed by shortening of the euglobulin clot lysis time. Therefore, YC-1 is an effective antithrombotic agent in preventing thrombosis in animal models, and its antiaggregating and additional profibrinolytic effects may be of potential clinical benefit in the treatment of thromboembolic diseases.

Adenosine Diphosphate↗
PubMed1997

Inhibition by abruquinone A of phosphoinositide-specific phospholipase C activation in rat neutrophils.

In rat neutrophils, formyl-Met-Leu-Phe (fMLP)-induced phosphate formation was inhibited by abruquinone A (IC50 value about 32.7 +/- 6.4 microM) as well as by a putative phospholipase C inhibitor, [6-[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole- 2,5-dione (U73122) (IC50 value about 11.3 +/- 1.2 microM). The reduction in inositol phosphate levels appeared to reflect inhibition of phospholipase C activity because the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) catalyzed by a soluble fraction from neutrophils was also inhibited by abruquinone A (IC50 value about 31.4 +/- 5.6 microM) over the same range of concentrations. Although abruquinone A alone induced Ca2+ and Mn2+ influx into neutrophils in Ca(2+)-containing medium, abruquinone A, like U73122, inhibited Ca2+ release (IC50 value about 23.5 +/- 0.5 microM) from internal stores in Ca(2+)-free medium. These results indicate that abruquinone A inhibits the activity of phosphoinositide-specific phospholipase C in neutrophils.

Animals↗
PubMed1997

Simulation of detachment of specifically bound particles from surfaces by shear flow.

The receptor-mediated adhesion of cells to ligand-coated surfaces is important in many physiological and biotechnological processes. Previously, we measured the detachment of antibody-coated spheres from counter-antibody- and protein A-coated substrates using a radial-flow detachment assay and were able to relate mechanical adhesion strength to chemical binding affinity (Kuo and Lauffenburger, Biophys. J. 65:2191-2200 (1993)). In this paper, we use "adhesive dynamics" to simulate the detachment of antibody-coated hard spheres from a ligand-coated substrate. We modeled the antibody-ligand (either counter-antibody or protein A) bonds as adhesive springs. In the simulation as in the experiments, beads attach to the substrate under static conditions. Flow is then initiated, and detachment is measured by the significant displacement of previously bound particles. The model can simulate the effects of many parameters on cell detachment, including hydrodynamic stresses, receptor number, ligand density, reaction rates between receptor and ligand, and stiffness and reactive compliance of the adhesive springs. The simulations are compared with experimental detachment data, thus relating measured bead adhesion strength to molecular properties of the adhesion molecules. The simulations accurately recreated the logarithmic dependence of adhesion strength on affinity of receptor-ligand recognition, which was seen in experiments and predicted by analytic theory. In addition, we find the value of the reactive compliance, the parameter which relates the strain of a bond to its rate of breakage, that gives the best match between theory and experiment to be 0.01. Finally, we analyzed the effect of varying either the forward or reverse rate constants as different ways to achieve the same affinity, and showed that adhesion strength depends uniquely on the equilibrium affinity, not on the kinetics of binding. Given that attachment is independent of affinity, detachment and attachment are distinct adhesive phenomena.

Cell Adhesion↗
PubMed1997

Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of 2-substituted 3-chloro-1,4-naphthoquinone derivatives.

A series of 2-substituted 3-chloro-1,4-naphthoquinones was synthesized, and the antiplatelet, antiinflammatory, and antiallergic activities of these compounds were evaluated. The structure-activity relationships in this series were also examined. Most of the 2-alkyl/arylcarboxamido derivatives of 3-chloro-1,4-naphthoquinone showed potent activities with similar trends in each of the activities evaluated.

Animals↗
PubMed1997

Inhibition by HAJ11 of respiratory burst in neutrophils and the involvement of protein tyrosine phosphorylation and phospholipase D activation.

1. The possible mechanisms of the inhibitory effect of ethyl 2-(3-hydroxyanilino)-4-oxo-4,5-dihydrofuran-3-carboxylate (HAJ11) on the respiratory burst of rat neutrophils in vitro was investigated. 2. HAJ11 caused a reversible and a concentration-dependent inhibition of formyl-Met-Leu-Phe (fMLP)-induced superoxide anion (O2.-) generation (IC50 4.9 +/- 0.7 microM) and O2 consumption (IC50 4.9 +/- 1.5 microM). Concanavalin A (Con A)- and NaF-induced O2.- generation were also suppressed by HAJ11. However, HAL11 was a weak inhibitor of the phorbol 12-myristate 13-acetate (PMA)-induced responses. 3. HAJ11 did not scavenge the /2.- generation in the xanthine-xanthine oxidase system and dihydroxyfumaric acid (DHF) autoxidation. 4. HAJ11 showed no activity on fMLP-induced inositol phosphates formation and [Ca2+]i elevation in intact neutrophils. In addition, HAJ11 had no effect on neutrophil cytosolic phospholipase C (PLC) activity. 5. HAJ11 reduced fMLP-induced phosphatidic acid (PA) (IC50 29.1 +/- 6.5 microM) and phosphatidylethanol (PE+) (IC50 22.6 +/- 1.9 microM) formation in a concentration-dependent manner. HAJ11 also reduced protein tyrosine phosphorylation in neutrophils stimulated by fMLP. 6. HAJ11 was a weak inhibitor of neutrophil cytosolic protein kinase C (PKC) activity, and had a negligible effect on brain PKC. Cellular cyclic nucleotides levels were not altered by HAJ11. In addition, HAJ11 did not affect protein kinase A (PKA) activity. 7. HAJ11 had not effect on the O2.- generation of PMA-activated and arachidonic acid (AA)-activated NADPH oxidase preparations. 8. Taken together these results indicate that the inhibition of respiratory burst by HAJ11 probably mainly occurs through inhibition of protein tyrosine phosphorylation and phospholipase D (PLD) activity.

Animals↗
PubMed1997

Cellular localization of the inhibitory action of abruquinone A against respiratory burst in rat neutrophils.

1. The possible mechanisms of action of the inhibitory effect of abruquinone A on the respiratory burst in rat neutrophils in vitro was investigated. 2. Abruquinone A caused an irreversible and a concentration-dependent inhibition of formylmethionylleucyl-phenylalanine (fMLP) plus dihydrocytochalasin B (CB)- and phorbol 12-myristate 13-acetate (PMA)-induced superoxide anion (O2.-) generation with IC50 values of 0.33 +/- 0.05 microgram ml-1 and 0.49 +/- 0.04 microgram ml-1, respectively. 3. Abruquinone A also inhibited O2 consumption in neutrophils in response to fMLP/CB and PMA. However, abruquinone A did not scavenge the generated O2.- in xanthine-xanthine oxidase system and during dihydroxyfumaric acid (DHF) autoxidation. 4. Abruquinone A inhibited both the transient elevation of [Ca2+]i in the absence of [Ca2+]o (IC50 7.8 +/- 0.2 micrograms ml-1) and the generation of inositol trisphosphate (IP3) (IC50 10.6 +/- 2.0 micrograms ml-1) in response to fMLP. 5. Abruquinone A did not affect the enzyme activaties of neutrophil cytosolic protein kinase C (PKC) and porcine heart protein kinase A (PKA). 6. Abruquinone A had no effect on intracellular guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels but decreased the adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 7. The cellular formation of phosphatidic acid (PA) and phosphatidylethanol (PEt) induced by fMLP/ CB was inhibited by abruquinone A with IC50 values of 2.2 +/- 0.6 micrograms ml-1 and 2.5 +/- 0.3 micrograms ml-1, respectively. Abruquinone A did not inhibit the fMLP/CB-induced protein tyrosine phosphorylation but induced additional phosphotyrosine accumulation on proteins of 73-78 kDa in activated neutrophils. 8. Abruquinone A inhibited both the O2.- generation in PMA-activated neutrophil particulate NADPH oxidase (IC50 0.6 +/- 0.1 microgram ml-1) and the iodonitrotetrazolium violet (INT) reduction in arachidonic acid (AA)-activated cell-free system (IC50 1.5 +/- 0.2 micrograms ml-1) 9. Collectively, these results indicate that the inhibition of respiratory burst in rat neutrophils by abruquinone A is mediated partly by the blockade of phospholipase C (PLC) and phospholipase D (PLD) pathways, and by suppressing the function of NADPH oxidase through the interruption of electron transport.

Animals↗
PubMed1997

Investigation of the inhibition by acetylshikonin of the respiratory burst in rat neutrophils.

1. The ability of acetylshikonin to inhibit the respiratory burst in rat neutrophils was characterized and the underlying mechanism of action was also assessed in the present study. 2. Acetylshikonin caused an irreversible and a concentration-dependent inhibition of formylmethionylleucyl-phenylalanine (fMLP) plus dihydrocytochalasin B (CB)- and phorbol 12-myristate 13-acetate (PMA)-induced superoxide anion (O2.-) generation with IC50 values of 0.48 +/- 0.03 and 0.39 +/- 0.03 microM, respectively. Acetylshikonin also inhibited the O2 consumption in neutrophils in response to fMLP/CB as well as to PMA. 3. Acetylshikonin did not scavenge the generated O2.- in the xanthine-xanthine oxidase system or during dihydroxyfumaric acid (DHF) autoxidation but, on the contrary, acetylshikonin enhanced the O2.- generation in these cell-free oxygen radical generating systems. 4. Acetylshikonin inhibited the formation of inositol trisphosphate (IP3) (39.0 +/- 7.8% inhibition at 10 microM, P < 0.05) in neutrophils in response to fMLP. 5. Both the neutrophil cytosolic protein kinase C (PKC) activity and the PMA-induced PKC associated with the membrane were unaffected by acetylshikonin. 6. Acetylshikonin did not affect the porcine heart protein kinase A (PKA) activity. Upon exposure to acetylshikonin, the cellular cyclic AMP level was decreased in neutrophils in response to fMLP. 7. The cellular formation of phosphatidic acid (PA) and, in the presence of ethanol, phosphatidylethanol (PEt) induced by fMLP/CB were inhibited by acetylshikonin (60.1 +/- 7.3 and 63.2 +/- 10.5% inhibition, respectively, at 10 microM, both P < 0.05). Moreover, acetylshikonin attenuated the fMLP/CB-induced protein tyrosine phosphorylation (about 90% inhibition at 1 microM). 8. In PMA-activated neutrophil particulate NADPH oxidase preparations, acetylshikonin did not inhibit, but enhanced, the O2.- generation in the presence of NADPH. However, acetylshikonin decreased the membrane associated p47phox in PMA-activated neutrophils (about 60% inhibition at 1 microM). 9. Collectively, these results suggest that the attenuation of protein tyrosine phosphorylation and a failure in the assembly of a functional NADPH oxidase complex probably contribute predominantly to the inhibition of respiratory burst in neutrophils by acetylshikonin. In contrast, the blockade of phospholipase C (PLC) and phospholipase D (PLD) pathways play only a minor role in this respect.

Animals↗
PubMed1997

Electrophysiological basis for the antiarrhythmic action and positive inotropy of HA-7, a furoquinoline alkaloid derivative, in rat heart.

1. HA-7, a new synthetic derivative of furoquinoline alkaloid, increased the contractile force of right ventricular strips and effectively suppressed the ischaemia-reperfusion induced polymorphic ventricular tachyrhythmias in adult rat heart (EC50 = 2.8 microM). 2. In rat ventricular myocytes, HA-7 concentration-dependently prolonged the action potential duration (APD) and decreased the maximal rate of rise of the action potential upstroke (Vmax). The action potential amplitude and resting membrane potential were also reduced, but to a smaller extent. The prolongation of APD by HA-7 was prevented by pretreating the cells with 1 mM 4-AP. 3. Voltage clamp experiments revealed that HA-7 decreased the maximal current amplitude of I(Na) (IC50 = 4.1 microM) and caused a negative shift of its steady-state inactivation curve and slowed its rate of recovery from inactivation. The use-dependent inhibition of I(Na) by HA-7 was enhanced at a higher stimulation rate. The L-type Ca2+ current (I(Ca)) was also reduced, but to a lesser degree (IC50 = 5.3 microM, maximal inhibition = 31.8%). 4. This agent also influenced the time- and voltage-dependent K currents. The prolongation of APD was associated with an inhibition of a 4-AP sensitive transient outward K current (I(to)) (IC50 = 2.9 microM) and a slowly inactivating, steady-state outward current (I(SS)) (IC50 = 2.5 microM). The inhibition of I(to) by HA-7 was associated with an acceleration of its time constant of inactivation. HA-7 suppressed I(to) in a time-dependent manner and caused a significant negative shift of the voltage-dependent steady-state inactivation curve but did not affect its rate of recovery from inactivation. 5. At higher concentrations, the inward rectifier K+ current (I(KI)) was also inhibited but to a less extent. Its slope conductance after 3, 10 and 30 microM HA-7 was decreased by 24+/-4%, 41+/-5% and 54+/-8%. respectively. 6. We conclude that HA-7 predominantly blocks I(to) and Na+ channels and that it also weakly blocks Ca2+ and I(KI) channels. These changes alter the electrophysiological properties of the heart and terminate the ischaemia reperfusion induced ventricular arrhythmia. The significant I(to) inhibition and minimal I(Ca) suppression may afford an opportunity to develop an effective antiarrhythmic agent linked with positive inotropy.

Alkaloids↗
PubMed1996

Inhibition of platelet function by A02131-1, a novel inhibitor of cGMP-specific phosphodiesterase, in vitro and in vivo.

The effect of A02131-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl thieno (3,2-c)pyrazole], a cGMP-specific phosphodiesterase (PDE) inhibitor, on platelet function was investigated. The compound was found to inhibit the aggregation of and adenosine triphosphate (ATP) release from human platelet-rich plasma and washed platelets that were induced by aggregation inducing drugs such as arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), adenosine diphosphate (ADP) and A23187, and the inhibitory effect was concentration-dependent. A02131-1 also disaggregated the performed platelet aggregates induced by these inducers. Thromboxane B2 (TXB2) formations caused by collagen, PAF, ADP, and A23187 were inhibited by A02131-1 at concentrations that did not affect the AA-induced formation of TXB2 and prostaglandin D2 (PGD2). A02131-1 suppressed both the generation of inositol 1,4,5-triphosphate (IP3) and the increase of intracellular Ca2+ concentration stimulated by these aggregation inducers. A02131-1 was shown to increase the cAMP and cGMP levels in platelets and the extent was found to be dependent on concentration as well as time. A02131-1 increased the cAMP level much more slowly than the cGMP level. Activities of adenylate cyclase, guanylate cyclase, and PDEs (type I and III) were not altered by A02131-1. However, the activity of cGMP-specific PDE (type V) was inhibited by A02131-1. The antiplatelet aggregation activity and the effect on raising cAMP level of A02131-1 were both potentiated by prostaglandin E1 (PGE1). In the mouse tail bleeding test, A02131-1 was clearly shown to be more effective than dipyridamole in prolonging the tail bleeding time of conscious mice. These data indicate that A02131-1 is a cGMP-specific PDE (type V) inhibitor in human platelets.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

Synthesis and cytotoxicity of 1,2-disubstituted naphth[2,3-d]imidazole-4,9-diones and related compounds.

As part of our continuing search for potential anticancer drug candidates that are selective against slowly growing solid tumors, we have synthesized several series of 1- and 2-substituted derivatives of the lead structure, 1-ethyl-2-methylnaphth[2,3-d]imidazole-4,9-dione (5). Their cytotoxic activity in the National Cancer Institute's in vitro cancer cell line panel is reported. In general, substitution of various alkyl, phenyl, or benzyl moieties did not improve activity, and compound 5 remains the most active naphth[2,3-d]imidazole-4,9-dione derivative. However, high levels of activity and selectivity were found with several related 2-(acylamino)-3-chloro-1,4-naphthoquinones (2f-j). Compound 2i, 2-[(2-fluorophenyl)acetamido]-3-chloro-1,4-naphthoquinone, has been selected for further in vivo testing and as an additional lead compound for further structural modification.

Antineoplastic Agents↗
PubMed1996

Inhibition of hind-paw edema and cutaneous vascular plasma extravasation by 2-chloro-3-methoxycarbonylpropionamido-1,4-naphthoquinone (PP1D1) in mice.

2-Chloro-3-methoxycarbonylpropionamido-1,4-naphthoquinone (PP1D1) produced a dose-dependent inhibition of the polymyxin B-induced hind-paw edema in normal as well as in adrenalectomized mice. A comparable inhibitory profile was observed in mice to which PP1D1 was injected i.p. or applied orally. Unlike dexamethasone, PP1D1 had no effect on the liver glycogen content in fasting adrenalectomized mice. Ear edema caused by passive cutaneous anaphylactic reaction, or by subcutaneous injection of compound 48/80, histamine, serotonin, bradykinin or substance P was reduced by PP1D1 in a dose-dependent manner. In addition, topical application of PP1D1 suppressed the capsaicin- and arachidonic acid-induced ear edema. In compound 48/80-pretreated mice, the tissue histamine content was greatly reduced. Under these conditions, PP1D1 reduced the bradykinin- and substance P-induced ear edema to a significantly greater extent than diphenhydramine plus methysergide. These results suggest that the inhibitory effect of PP1D1 on the edematous response is due to the protection of the microvasculature from mediator challenge.

Animals↗