-
[show abstract]
[hide abstract]
ABSTRACT: Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN-MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy.
Nanoscale 05/2013; · 5.91 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Alsterpaullone, a small molecule cyclin-dependent kinase (CDK) inhibitor, regulates the cell cycle progression. Beyond death-inducing properties, we identified the effect of alsterpaullone on cycle procedure and apoptosis of HeLa cell. It was found that alsterpaullone inhibited HeLa cells in a time-dependent (0-72 h) and dose-dependent (0-30 μ M) manner. In the presence of alsterpaullone, HeLa cells were arrested in G2/M prior to undergoing apoptosis via a mechanism that is involved in the regulation of various antiapoptotic genes, DNA-repair, transcription, and cell cycle progression. Compared to controls, alsterpaullone effectively prevented HeLa cells from entering S-phase. These potential therapeutic efficacies could be correlated with the activation of caspase-3.
Journal of analytical methods in chemistry. 01/2013; 2013:602091.
-
[show abstract]
[hide abstract]
ABSTRACT: THE ANTITUMOR ACTIVITY OF ROSCOVITINE WAS TESTED IN FOUR CERVICAL CARCINOMA CELLS: C33A, HCE-1, HeLa, and SiHa. The effects of roscovitine on ATP Lite assay, cell cycle, and apoptosis were assessed. The Sub-G1 DNA content occurred great increasing, and this indicates that apoptosis was induced quickly in HeLa cells, but slowly in the other cells. The morphological observation results showed that roscovitine induced apoptosis and cell death in the cervical carcinoma cells. Results revealed that roscovitine exhibited selective cytotoxicity towards 4 cervical carcinoma cells, and the cells showed different morphologic and apoptotic changes at the same concentration. It was estimated that cervical carcinoma cells responded differently to roscovitine because of differences in apoptotic and genetic background in different cervical carcinoma cells. This study suggested that roscovitine had the potential to be a chemotherapeutic agent against cervical carcinoma.
Journal of analytical methods in chemistry. 01/2013; 2013:389390.
-
[show abstract]
[hide abstract]
ABSTRACT: Poly-α,β-dl-aspartic acid is known as a green chelant of various metal ions. To provide a novel nanochelant for treating Pb(II) poisoning, poly-α,β-dl-aspartic acid was modified with l-Cys to form poly-α,β-dl-aspartyl-l-cysteine (PDC; MW, 27273). dl-Asp was converted into polysuccinimide through a thermal polycondensation, and the amidation of polysuccinimide with l-Cys provided PDC. In water, PDC formed various porous nanospecies. In the mouse lead intoxication model, both intraperitoneal and oral administration of PDC (0.1, 1.0, and 10.0 nmol/kg) dose dependently removed Pb(II) accumulated in the organ, bone, and blood. PDC did not remove the essential metals including Cu(2+), Fe(2+), Mn(2+), Zn(2+), and Ca(2+) of the treated mice. The porous feature and size of the pH- and concentration-dependent nanospecies of PDC benefited the removal of Pb(II).
Chemical Research in Toxicology 08/2012; 25(9):1948-54. · 3.78 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Platelet surface glycoproteins P-selectin and GPIIb/IIIa are implicated in the formation of platelet-fibrin-leukocyte thrombus and platelet-fibrin-platelet thrombus, respectively. In the current study, taking N-(3S-tetrahydroisoquinoline-3-carbonyl)-Thr-Ala-Arg-Gly-Asp-(Phe)-Phe (IQCA-TAFF) as a model compound, the molecular modeling, synthesis, and an evaluation system for a novel anti-thrombotic agent were investigated. The synthesis of IQCA-TAFF was achieved by coupling 3S-tetrahydro-isoquinoline-3-carboxylic acid (IQCA) and Thr-Ala-Arg-Gly-Asp(Phe)-Phe (TAFF). The molecular modeling indicated that IQCA-TAFF was able to occupy the active site pocket of P-selectin with its IQCA moiety and to block GPIIb/IIIa fibrinogen-binding sites with its TAFF moiety, respectively. These are consistent with the dual inhibition of the expressions of P-selectin and GPIIb/IIIa, and with the in vitro anti-platelet aggregation activity of IQCA-TAFF. Besides, the dual suppression of P-selectin and GPIIb/IIIa leads to significant in vivo efficacy of IQCA-TAFF, 500-fold higher than those of IQCA and TAFF, respectively. Transmission electron microscopy (TEM) images indicated that in water, IQCA-TAFF concentration-dependently formed nano-globes. The molecular modeling, in vitro bioassay, in vivo bioassay, action mechanism investigation, and nano-image visualization together constitute a model system to characterize the anti-thrombotic agent capable of simultaneously inhibiting P-selectin and GPIIb/IIIa mediated thrombosis.
Molecular BioSystems 07/2012; 8(10):2672-9. · 3.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To clarify the relationships of the commonly used spectral measurements and the in vivo activity of β-carboline intercalators
N-[2(3-carboxyl-9-benzyl-carboline-1-yl)ethyl-1-yl]-aspartic acid (3a), -tyrosine (3b), -serine (3c), and -threonine (3d) were prepared as the model compounds by using a three-step procedure. In UV measurements of calf thymus DNA (CT DNA) the
in vivo active 3a–c induced both hypochromic effect and hypsochromic shift, while the in vivo inactive 3d did not. In CD measurements the in vivo active 3a–c changed the intensities of both positive and negative bands of CT DNA in same direction, while the in vivo inactive 3d induced an opposite change. In fluorescence measurements due to adding CT DNA the increase of the fluorescence intensities
of 3a–c were 10–31% higher than that of 3d, and the bathochromic shifts of 3a–c were 2–6nm higher than that of 3d. The viscositic experiments revealed that 3d possessed the lowest binding ratio. The melting curves indicate that the effect of 3a–c (ΔT
m, 10.8–12.9°C) on the T
m of CT DNA was significantly higher than that of 3d (ΔT
m, 4.9°C). Spectroscopic, viscositic, and melting curve investigations are not only able to provide multiple evidences for
DNA intercalation mechanism, but also are able to distinguish the in vivo active and inactive N-[2(3-carboxyl-9-benzyl-carboline-1-yl)-ethyl-1-yl]-amino acids.
Keywordsβ-Carboline–Anti-tumor–Intercalator–Spectral measurement
Medicinal Chemistry Research 04/2012; 21(1):116-123. · 1.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To discover whether novel anti-tumor platinum agents are capable of selectively accumulating in tumor tissue, three novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) were prepared. At a dose of 1.67 μmol kg(-1) the in vivo anti-tumor potencies of two of the compounds were higher than that of oxaliplatin. The mortality analysis indicated that these compounds resulted in a 100% survival rate, whereas oxaliplatin lead to an 80% survival rate. The organ damage examination indicated that these compounds induced less damage than oxaliplatin. The platinum accumulation in the organs, blood and bone was significantly lower than that of oxaliplatin treated mice, while the platinum accumulation in the tumor tissue was significantly higher than that of the oxaliplatin treated mice.
Metallomics 04/2012; 4(5):441-7. · 3.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To increase the metal selectivity of polyaspartic acid, a so-called green chelant, poly-α,β-dl-aspartyl-l-methionine (PDM) was synthesized as a novel lead chelating agent. The phosphoric acid (80%) catalyzed thermal poly condensation of dl-aspartic acid provided poly succinimide, which was amidated with l-methionine to form PDM (MW: 29161). At the doses of 0.1, 1.0, and 10.0 nmol/kg, either by intraperitoneal injection (i.p.) or oral administration, PDM removed Pb from the spleens, hearts, and kidneys of mice, especially dose-dependently decreasing the accumulation of Pb in the brains, livers, and femurs of the mice, and did not interfere with the essential metals, including Cu, Fe, Mn, and Ca. Even at the dose of 0.1 nmol/kg, the i.p. injection of PDM removed Pb from the spleens, hearts, and kidneys of mice and increased the amount of urinary volume and urinary Pb, and the amount of fecal matter and the amount of fecal Pb, resulting in effective removal of Pb from the body of mice given Pb by i.p. injection. Our findings revealed that in aqueous solution PDM formed diverse nanospecies.
Chemical Research in Toxicology 02/2012; 25(2):471-7. · 3.78 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with β-cyclodextrin (β-CD) provides an oral antithrombotic agent, 6-(3'S-isoquinoline-3'-carboxylaminoethylamino)-6-deoxy-β-CD (THIQA-β-CD). In aqueous solution THIQA-β-CD undergoes intermolecular inclusion complexation and forms pH-dependent nanostructures. The morphological feature of THIQA-β-CD is a nanocloud consisting of numerous particles that are 5 nm-6 nm in diameter at pH 3.0. The nanocloud switches to a nanorod ranging from 100 nm to 385 nm in length at pH 7.2, then to nanowires of 50 nm to 530 nm in length at pH 10.1. THIQA-β-CD, which has unusual nanostructures, offers enhanced stability in blood. Inhibition of thrombin-induced platelet aggregation in vitro and demonstrated antithrombotic efficacy in vivo. This investigation demonstrated that the modification of THIQA with β-CD is a promising approach for clinical therapy of thrombus disease. The pH-dependent nanostructures of conjugate provide the desired in vivo antithrombotic activity and in vitro stability in blood. FROM THE CLINICAL EDITOR: This study a demonstrates that the modification of 3S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (THIQA) with beta-cyclodextrin, which leads to pH dependent nanostructure formation, is a promising approach for clinical therapy of thrombotic disease.
Nanomedicine: nanotechnology, biology, and medicine 01/2012; 8(7):1216-22. · 5.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Current clinically used chemotherapeutic platinum drugs can trigger severe toxic effects. To develop a model system for the evaluation of the therapeutic efficacy and the toxic effects of new platinum agents, we have synthesized a new compound N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-hydroxyproline dichloroplatinum(ii) (PHDP), compared its in vitro anti-proliferation activity, in vivo anti-tumor activity and safety to those of oxaliplatin, and correlated all these biological actions with the platinum occurring in the spleen, kidney, heart, brain, blood, tumor tissue, urine and faeces of the treated mice. We explored the atomic absorption based determinations of the platinum which occurred in the spleen, kidney, heart, brain, blood, tumor tissue, urine and faeces and constitute a model system that can be generally used in the investigation of the novel platinum agents.
Molecular BioSystems 12/2011; 7(12):3245-52. · 3.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: High anti-thrombotic activity of aminoacid modified tetrahydro-β-carbolines was generally correlated with a small proximity of the side chain of the aminoacid residue to the carboline-cycle. This paper explored that the aromatization of the tetrahydro-β-carboline-cycle of N-(1-methyl-β-tetrahydrocarboline-3-carbonyl)-N'-(aminoacid-acyl)-hydrazines leaded to N-(1-methyl-β-carboline-3-carbonyl)-N'-(aminoacid-acyl)-hydrazines and decreased the proximity of the side chain of the aminoacid residue to the carboline-cycle. The in vitro activities of inhibiting pig platelet aggregation induced by PAF, ADP, and AA, as well as the in vivo anti-thrombotic activities of inhibiting rat thrombosis of these aromatized derivatives were generally higher than that of N-(1-methyl-β-tetrahydrocarboline-3-carbonyl)-N'-(aminoacid-acyl)-hydrazines. The understanding was also obtained from the 3D QSAR analysis.
European journal of medicinal chemistry 11/2011; 46(11):5598-608. · 3.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Antifibrinolytic agents are required during complex surgeries to decrease bleeding; their pro-thrombotic potency and efficacy in causing hemostasis has attracted much attention. To discover new inhibitors of urokinase with high selectivity for antifibrinolytic effects over pro-thrombotic effects, the 12-position of (5aS,12S,14aS)- and (5aS,12R,14aS)-5,14-dioxo-1,2,3,5,5a,6,11, 12,14,14a-decahydro-5H,14H-pyrolo[1,2:4,5]pyrazino[1,2:1,6]pyrido[3,4-b]indoles were modified with L-Ala, L-Asp, L-Phe, L-Trp, L-Lys, L-Ser, Gly, and L-Leu to provide 16 (5aS,12S,14aS) and (5aS,12R,14aS) derivatives. In a murine bleeding model, the (5aS,12S,14aS) derivatives containing L-Ala, L-Asp, L-Phe, and L-Trp induced blood coagulation for the treated mice; they also stimulated thrombus formation in a rat thrombosis model, but the other derivatives inhibited thrombosis. The most potent compound, the L-Asp derivative, showed a good therapeutic window: the minimum effective dose for coagulation was <1 nmol kg(-1), whereas at 10 nmol kg(-1), no pro-thrombotic effect was observed. This type of coagulation action was correlated with a mechanism of urokinase inhibition, and these results could lead to the discovery of novel urokinase inhibitors.
ChemMedChem 09/2011; 6(12):2312-22. · 3.15 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In China the leaves of Rabdosia rubescens have been cooked in water and widely drank to treat inflammatory and pain related diseases. To explore the components that were possibly absorbed by people the aqueous extract of the leaves was prepared, and one single HPLC-PDA/(-)ESI-MS/MS analysis was developed to simultaneously determine the components. Using the HPLC-PDA analysis 39 peaks were found in the aqueous extract, while using the (-)ESI-MS/MS analysis we were able to identify 30 peaks represented components, including 5 nucleic acids, 21 phenolic acids and 4 diterpenoids. On mouse models the in vivo anti-inflammation and analgesic actions demonstrate that 0.32 g/kg of the aqueous extract of the leaves of Rabdosia rubescens can effectively inhibit the inflammation-induced chronic pain.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 09/2011; 879(26):2783-93. · 2.78 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Antifibrinolytic therapy during major complex surgery could reduce blood loss and allogeneic transfusion. Novel antagonists of the plasminogen activator and the corresponding model system are of clinical importance. In this paper (1S,2'S,3S)-1-[2-(S)-carboxylindolemethylenemethineaminoeth-1-yl]-2,3,4,5-tetrahydropyrolo[1,2:1,6]pyrazino[3,4:2,3]-1,2,3,4-tetrahydrocarboline-2,5-dione (CIPPC) was presented as a novel antagonist of plasminogen activator, and its blood coagulation and action mechanism were investigated by using a model system which consisted of a mouse-tail bleeding assay, in vitro and in vivo fibrinolysis inhibition assays, a thrombus formation assay and a plasminogen (PLG) electrophoresis assay.
Molecular BioSystems 09/2011; 7(9):2664-9. · 3.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The in vivo anti-thrombotic activities of amino acid modified tetrahydro-β-carbolines depended upon the proximity of the side chain of the amino acid residue to the carboline-cycle. Based on this proximity the computerized screening of various tetrahydro-β-carboline derivatives was performed and N-[(1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carbonyl]-N'-(amino-acid-acyl)hydrazines were explored having large proximity. The in vivo anti-thrombotic assays explored that at a dose of 10 nmol/kg eighteen novel N-[(1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carbonyl]-N'-(amino-acid-acyl)hydrazines were orally efficacious.
European journal of medicinal chemistry 08/2011; 46(8):3237-49. · 3.27 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: From the anti-tumor active N-tryptophanyl-β-carboline-3-carboxylic acid benzyl ester and β-carboline-3-carbonyltryptophan benzyl ester, a pharmacophore, Trp-Trp-OBzl, was drawn. Based on the DOCK scores amino acid residue was inserted into the C-terminus of Trp-Trp-OBzl and twenty Trp-Trp-AA-OBzls (AA = amino acid residues) were provided as DNA intercalators. On the in vitro and in vivo models seventeen Trp-Trp-AA-OBzls were anti-tumor active, and twelve Trp-Trp-AA-OBzls were more active than cytarabine. In acute toxicity assay Trp-Trp-AA-OBzls did not damage the immunologic function and had an LD(50) of more than 500 mg/kg. The relationships of structure and activity were analyzed with 3D QSAR. The action mechanism studies revealed that the in vivo anti-tumor action of Trp-Trp-AA-OBzls was the result of DNA intercalation.
European journal of medicinal chemistry 08/2011; 46(8):3410-9. · 3.27 Impact Factor
-
Yanxia Xu,
Yuji Wang,
Ling Wang,
Ming Zhao,
Xiaoyi Zhang,
Xiaomin Hu,
Baoguang Hou,
Li Peng,
Meiqing Zheng,
Jianhui Wu, Shiqi Peng
[show abstract]
[hide abstract]
ABSTRACT: The coupling of the 1-carboxyl of DMSA with l-amino acids led to a class of novel 1-(carbonyl-l-amino-acid)-2,3-dimercaptosuccinic acids (DMSA--amino acid conjugates, DMSA-Gly, -Ser, -Val, -Leu, -Ile, -Asn, -Asp, -Gln, -Glu, -Met, -Phe, and -Trp). In the in vivo evaluation of Pb-loaded mice, 0.4 mmol/kg of the conjugates effectively decreased the Pb levels of the femur, brain, kidney, liver, and blood, greatly enhanced urination, and increased the Pb levels of both urine and feces, while causing no redistributions of Pb to the other organs, especially to the brain. With respect to lowering the bone and brain Pb, DMSA-Ile, -Asn, -Gln, and -Met were more effective than DMSA. This benefit was attributed to their high transmembrane ability. In contrast to Pb, the essential metals such as Fe, Cu, Zn, and Ca of the treated mice were not affected by the administration of the conjugates. Silico molecular modeling predicted that the conjugates had little hepatotoxicity, except possibly for DMSA-Phe.
Chemical Research in Toxicology 06/2011; 24(6):979-84. · 3.78 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A series of chelants (3a-s) composed of a glucosyl tail, an amino acid side chain and a dithiocarbamate group were designed, synthesized, and evaluated. By co-administering with cisplatin, 3a-s were able to decrease the accumulation of platinum in the organs, maintain the accumulation of platinum in the tumor tissues, and increase the urinary and fecal platinum, as well as increasing the voided volume of the treated S180-bearing mice. Compared to S180-bearing mice treated with cisplatin alone, the co-administered mice lost no spleen, kidney, liver, brain and heart weights, lost less body weight, and showed no increase in tumor weight.
Metallomics 05/2011; 3(11):1212-7. · 3.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A convenient synthesis of 2-amino-3,4,6-tri-O-benzyl-2-deoxy-β-d-glucopyranoside was described from the readily available starting material 2-acetamido-2-deoxy-d-glucose (N-acetyl-d-glucosamine). Herein, the coupling of different lipophilic amino acids with 2-amino-3,4,6-tri-O-benzyl-2-deoxy-β-d-glucose was reported via an amide linkage as useful building blocks for the synthesis of glycopeptides. Of particular interest, bioactive peptide Arg-Gly-Asp (RGD) was incorporated into the building block containing valine was also reported. The 15 examples of corresponding di-, tri- and tetra-peptides were obtained as single αanomers.
Carbohydrate research 04/2011; 346(13):1997-2003. · 2.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: {2-[1-(3-Methoxycarbonylmethyl-1H-indol-2-yl)-1-methyl-ethyl]-1H-indol-3-yl}-acetic acid methyl ester (MIAM) was provided as a DNA-intercalator. For the comprehensive evaluation of this new intercalator, an assay system consisting of cell, S180 mouse, healthy mouse, spectrum, non-spectrum, and gel electrophoresis models was constructed. On the cell (S180, K562, MCF-7, HeLa and HepG2) models, MIAM selectively inhibited the viability of HeLa. On the S180 mouse model, 0.89, 8.9, 89 and 890 μmol kg(-1) of MIAM dose-dependently inhibited the tumor growth. Even at a dose of 890 μmol kg(-1), MIAM did not damage the treated S180 mice. The safety of MIAM was supported by a high spleen index and an obvious increase of body weight of the treated S180 mice. On the healthy mouse model the LD(50) value of MIAM is higher than 890 μmol kg(-1). The ultraviolet (UV), fluorescence, circular dichroism (CD), relative viscosity, melting curve, and gel electrophoresis assays of DNA with or without MIAM consistently supported an intercalation mechanism for MIAM.
Molecular BioSystems 03/2011; 7(3):766-72. · 3.53 Impact Factor
