Meiqing Zheng

A class of novel N-(3S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-amino acid derivatives: their synthesis, anti-thrombotic activity evaluation, and 3D QSAR analysis

To find new anti-thrombotic agents, a natural amino acid was introduced into the 3-position of anti-platelet aggregation active 3S-tetrahydroisoquinoline-3-carboxylic acid (THIQA), and 20 novel dipeptide derivatives, 3S-tetrahydroisoquinoline-3-carboxyamino acids (6a-t), targeting the intestinal peptide transport system were provided. In vitro anti-platelet aggregation assay of 6a-t indicated that their potencies of inhibiting adenosine diphosphate (ADP), arachidonic acid (AA), platelet-activating factor (PAF), and thrombin (TH) induced platelet aggregations were higher than that of THIQA, and the in vivo anti-thrombotic assay of 6a-t indicated that their potencies of inhibiting thrombogenesis in rats were also higher than that of THIQA. According to MFA based Cerius2 QSAR module, using training/test set of 6a,b,d,g-p/6c,e,f,q and training/test set of 6a-p/6q-t, two equations (r, 0.984 and 0.996) correlating the structures with in vitro or in vivo activity of 6a-t were established.

(3S)-N-(L-Aminoacyl)-1,2,3,4-tetrahydroisoquinolines, a class of novel antithrombotic agents: synthesis, bioassay, 3D QSAR, and ADME analysis.

To increase antithrombotic activity, 3S-tetrahydroisoquinoline-3-carboxylic acid (1) was modified with natural amino acids to form 19 novel dipeptide analogs, 3S-tetrahydroisoquinoline-3-carboxyamino acids (5a-s), targeting the intestinal peptide transport system. In vitro assay of 5a-s indicated that their potencies for inhibiting adenosine diphosphate (ADP), arachidonic acid (AA), platelet-activating factor (PAF), and thrombin (TH)-induced platelet aggregations were higher than that of 1. Additionally, in vivo assay of 5a-s indicated that their potencies for inhibiting thrombogenesis in rats were also higher than that of 1. Among the candidates, 5h with Ser attachment showed the most impressive features for further development. According to molecular field analysis based Cerius(2) QSAR module, two equations (r, 0.961 and 0.988) correlating the structures with both in vitro and in vivo activities of 5a-s were established. ADMET calculations predict higher intestinal absorption for compounds 5a-s. Further investigation with 5h as a lead compound is underway.

2,3-Diamino acid modifying 3S-tetrahydroisoquinoline-3-carboxylic acids: Leading to a class of novel agents with highly unfolded conformation, selective in vitro anti-platelet aggregation and potent in vivo anti-thrombotic activity

In the preparation of anti-thrombotic agents the 2- and 3-positions of 3S-tetra-hydroisoquinoline-3-carboxylic acid (THIQA) were simultaneously modified with amino acids to form 20 novel N-(3S-N-aminoacyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino acids (8a-t). On an in vitro platelet aggregation model 8a-t selectively inhibit ADP-induced platelet aggregation and their IC(50) values are leas than 3.5 nM. On an extracorporeal circulation of arterioveinos cannula model of rats both orally and intraveously effective doses of 8a-t are less than 30 nmol/kg. Cerius(2) based stereoview of explores 8a-t having highly unfolded conformation. 3D QSAR analysis gives the importance of the unfolded conformation to high in vitro anti-platelet aggregation and in vivo anti-thrombotic potency rational understanding.

A Class of 3S-2-Aminoacyltetrahydro-β-carboline-3-carboxylic Acids: Their Facile Synthesis, Inhibition for Platelet Activation, and High in Vivo Anti-Thrombotic Potency

3S-Tetrahydro-beta-carboline-3-carboxylic acid (TCCA) effectively inhibits ADP-induced platelet activation. This paper used TCCA as a lead, modified its 2-position with amino acids, and provided 20 novel 3S-2-aminoacyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acids (5a-t). With the in vitro assay, it was demonstrated that this modification diminished the IC(50) values from 701 nM of TCCA to 10 nM of 5a-t. With the in vivo assay, it was demonstrated that this modification reduced the efficacious dose from 5.0 micromol/kg of TCCA to 0.1 micromol/kg of 5a-t. Comparing the Cerius based conformation of them with that of their analogues, the 3-position modified TCCA, it was suggested that the comparatively unfolded conformation was one of the important factors of enhancing the in vivo antithrombotic potency.

One single HPLC-PDA/(-)ESI-MS/MS analysis to simultaneously determine 30 components of the aqueous extract of Rabdosia rubescens

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.

The application of tetrahydroisoquinoline-3-carbonyl-TARGD(F)F as an anti-thrombotic agent having dual mechanisms of action

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.

Synthesis and in vivo lead detoxification evaluation of Poly-α,β-dl-aspartyl-l-methionine.

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.

A class of novel N-isoquinoline-3-carbonyl-l-amino acid benzylesters: Synthesis, anti-tumor evaluation and 3D QSAR analysis

Isoquinoline-3-carboxylic acid (2) was modified with amino acid benzylesters and 18 novel N-isoquinoline-3-carbonylamino acid benzylesters (3a-r) were provided. The IC50 values of 3a-r against the proliferation of HL-60 and Hela cells were less than 1×10(-8) M and 6×10(-7) M, respectively. On S180 mice model 100 μmol/kg of 3a-r effectively inhibited the growth of the tumors. Using MFA based Cerius2 QSAR module, two equations (r, 0.989 and 0.987) were established to correlate the structure with the in vitro and in vivo activities. The benefit of this modification was supported with both the in vitro membrane permeation test and the in vivo anti-tumor assay. The in vitro membrane permeability of N-isoquinoline-3-carbonyl-l-threonine benzylester (3n) and N-isoquinoline-3-carbonyl-l-leucine benzylester (3q) was 2.5 fold higher than that of 2, and the in vivo anti-tumor activity of 3n, q was 4.4-fold higher than that of 2.

Lead detoxification activities of a class of novel DMSA--amino acid conjugates.

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.

Lead detoxification activities and ADMET hepatotoxicities of a class of novel 5-(1-carbonyl-l-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids

By linking the mercapto groups with isopropyl and introducing L-amino acid into the 5-carboxyl of DMSA a class of novel 5-(1-carbonyl-L-amino-acid)-2,2- dimethyl-[1,3]dithiolane-4-carboxylic acids were prepared. Their in vivo activities were evaluated on lead loaded mice at the dose of 0.4 mmol/kg. The results showed that the lead levels of the livers, kidneys, femurs and brains in particular could be efficiently decreased by 0.4 mmol/kg of 5-(1-carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids. The benefit of 5-(1-carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids to the detoxification of the brain lead was attributed to their transmembrane ability. Compared with the lead detoxification efficacy, they did not affect the essential metals such as Fe, Cu, Zn, and Ca of the treated mice. Silico molecular modeling predicted that 5-(1-carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids had no hepatotoxicity.