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1.
Molecules ; 26(20)2021 Oct 14.
Article in English | MEDLINE | ID: mdl-34684780

ABSTRACT

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Triazoles/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Benzocycloheptenes/chemistry , Benzocycloheptenes/metabolism , Binding Sites , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Databases, Chemical , Half-Life , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Protein Binding , Quantitative Structure-Activity Relationship , SARS-CoV-2/isolation & purification , Triazoles/metabolism , Triazoles/therapeutic use , COVID-19 Drug Treatment
2.
J Am Chem Soc ; 141(33): 13038-13042, 2019 08 21.
Article in English | MEDLINE | ID: mdl-31389237

ABSTRACT

A rhodium-catalyzed direct insertion of ethylene into a relatively unstrained carbon-carbon bond in 1-indanones is reported, which provides a two-carbon ring expansion strategy for preparing seven-membered cyclic ketones. As many 1-indanones are commercially available and ethylene is inexpensive, this strategy simplifies synthesis of benzocycloheptenones that are valuable synthetic intermediates for bioactive compounds but challenging to prepare otherwise. In addition, the reaction is byproduct-free, redox neutral, and tolerant of a wide range of functional groups, which may have implications on unconventional strategic bond disconnections for preparing complex cyclic molecules.


Subject(s)
Benzocycloheptenes/chemical synthesis , Ethylenes/chemistry , Indans/chemistry , Benzocycloheptenes/chemistry , Carbon/chemistry , Catalysis , Cycloheptanes/chemical synthesis , Cycloheptanes/chemistry , Ethylenes/chemical synthesis , Indans/chemical synthesis , Rhodium/chemistry
3.
Curr Top Med Chem ; 19(13): 1129-1144, 2019.
Article in English | MEDLINE | ID: mdl-31109278

ABSTRACT

BACKGROUND: Lung cancer is the most common among all the types of cancer worldwide with 1.8 million people diagnosed every year, leading to 1.6 million deaths every year according to the American cancer society. The involvement of mutated Anaplasic Lymphoma Kinase (ALK) positive fusion protein in the progression of NSCLC has made a propitious target to inhibit and treat NSCLC. In the present study, the main motif is to screen the most effective inhibitor against ALK protein with the potential pharmacological profile. The ligands selected were docked with Molegro Virtual Docker (MVD) and CEP-37440 (PubChem CID- 71721648) was the best docked pre-established compound with a permissible pharmacological profile. METHODS: The selected ligands were docked with Molegro Virtual Docker (MVD). With reference to the obtained compound with the lowest re-rank score, PubChem database was virtually screened to retrieve a large set of similar compounds which were docked to find the compound with higher affinity. Further comparative studies and in silico prediction included pharmacophore studies, proximity energy parameters, ADMET and BOILED-egg plot analysis. RESULTS: CEP-37440 (PubChem CID- 71721648) was the best docked pre-established compound with preferable pharmacological profile and PubChem compound CID-123449015 came out as the most efficient virtually screened inhibitor. Interestingly, the contours of the virtual screened compound PubChem CID- 123449015 fall within our desired high volume cavity of protein having admirable property to control the ALK regulation to prevent carcinogenesis in NSCLC. BOILED-Egg plot analysis depicts that both the compounds have analogous characteristics in the divergent aspects. Moreover, in the evaluations of Blood Brain Barrier, Human Intestinal Absorption, AMES toxicity, and LD50, the virtually screened compound (PubChem CID-123449015) was found within high optimization. CONCLUSION: These investigations denote that the virtually screened compound (PubChem CID- 123449015) is more efficient to be a better prospective candidate for NSCLC treatment having good pharmacological profile than the pre-established compound CEP-37440 (PubChem CID- 71721648) with low re-rank score. The identified virtually screened compound has high potential to act as an ALK inhibitor and can show promising results in the research of non-small cell lung cancer (NSCLC).


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Benzocycloheptenes/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Computer-Aided Design , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Anaplastic Lymphoma Kinase/genetics , Anaplastic Lymphoma Kinase/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzamides/chemical synthesis , Benzamides/chemistry , Benzocycloheptenes/chemical synthesis , Benzocycloheptenes/chemistry , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Humans , Ligands , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Molecular Structure , Mutation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
4.
Mini Rev Med Chem ; 19(13): 1068-1079, 2019.
Article in English | MEDLINE | ID: mdl-30836912

ABSTRACT

BACKGROUND & OBJECTIVE: Six novel complexes of transition metal namely, [CoLCl2(H2O)2]0.5H2O, [NiLCl2(H2O)2]0.5H2O, [CuLCl2]0.5H2O, [ZnLCl2], [PdLCl2]H2O and [CdLCl2]H2O, where L is benzocycloheptenone thiosemicarbazone ligand, have been obtained. The confirmation of the structures of the obtained metal chelates depends on the different spectral and physicochemical techniques including CHN analysis, infrared spectra, molar conductivity measurement, UV-vis, thermogravimetric analysis and magnetic moment. The infrared spectral results ascertained that the ligand behaved as neutral bidentate connecting the metal centers via N and S atoms of C=N and C=S groups, respectively. METHODS: The UV-Vis, molar conductivity and magnetic susceptibility results implied that the geometrical structures of the metal chelates are octahedral for Co(II) & Ni(II) complexes, tetrahedral for Zn(II) & Cd(II) complexes and square planar for Cu(II) & Pd(II) complexes which have been confirmed by molecular modeling studies. CONCLUSION: Moreover, the mode of interaction between some chosen metal complexes towards SSDNA has been thoughtful by UV-Vis spectra and viscosity measurements. The value of the intrinsic binding constant (Kb) for the examined compounds has been found to be lower than the binding affinity of the classical intercalator ethedium bromide. Also, the viscosity measurements of the complexes proved that they bind to DNA, most likely, by a non-intercalative mode like H-bonding or electrostatic interactions.


Subject(s)
Benzocycloheptenes/chemistry , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , DNA, Single-Stranded/chemistry , Thiosemicarbazones/chemistry , Transition Elements/chemistry , Benzocycloheptenes/pharmacology , Binding Sites/drug effects , Coordination Complexes/pharmacology , DNA, Single-Stranded/drug effects , Ligands , Models, Molecular , Molecular Structure , Thiosemicarbazones/pharmacology , Transition Elements/pharmacology
5.
J Agric Food Chem ; 65(48): 10473-10481, 2017 Dec 06.
Article in English | MEDLINE | ID: mdl-29131612

ABSTRACT

Epitheaflagallin (ETFG) and epitheaflagallin 3-O-gallate (ETFGg) are minor polyphenols in black tea extract that are enzymatically synthesized from epigallocatechin (EGC) and epigallocatechin gallate (EGCg), respectively, in green tea extract via laccase oxidation in the presence of gallic acid. The constituents of laccase-treated green tea extract in the presence of gallic acid are thus quite different from those of nonlaccase-treated green tea extract: EGC and EGCg are present in lower concentrations, and ETFG and ETFGg are present in higher concentrations. Additionally, laccase-treated green tea extract contains further polymerized catechin derivatives, comparable with naturally fermented teas such as oolong tea and black tea. We found that ETFGg and laccase-treated green tea extracts exhibit versatile physiological functions in vivo and in vitro, including antioxidative activity, pancreatic lipase inhibition, Streptococcus sorbinus glycosyltransferase inhibition, and an inhibiting effect on the activity of matrix metalloprotease-1 and -3 and their synthesis by human gingival fibroblasts. We confirmed that these inhibitory effects of ETFGg in vitro match well with the results obtained by docking simulations of the compounds with their target enzymes or noncatalytic protein. Thus, ETFGg and laccase-treated green tea extracts containing ETFGg are promising functional food materials with potential antiobesity and antiperiodontal disease activities.


Subject(s)
Benzocycloheptenes/chemistry , Camellia sinensis/chemistry , Gallic Acid/chemistry , Laccase/chemistry , Plant Extracts/chemistry , Polyphenols/chemistry , Biocatalysis , Enzyme Inhibitors/chemistry , Lipase/antagonists & inhibitors , Lipase/chemistry , Oxidation-Reduction
6.
ChemMedChem ; 12(15): 1212-1222, 2017 08 08.
Article in English | MEDLINE | ID: mdl-28749574

ABSTRACT

Antagonists that selectively target GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen-7-amines and their GluN2B affinity were investigated. 2-Nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (8) represents the central building block for the introduction of various substituents at the 2-position and various 7-amino moieties. N-(3-Phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amines with a 2-NO2 (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (Ki =1.6-3.6 nm). Docking studies revealed the same binding poses for benzo[7]annulen-7-amines and ifenprodil at the interface of GluN1b and GluN2B subunits. The large 2-OBn moiety of 22 c occupies a previously unrecognized subpocket, which explains its high GluN2B affinity (Ki =3.6 nm). In two-electrode voltage clamp experiments and cytoprotection assays, the high-affinity GluN2B ligands 7 c, 15 c, and 22 c could not inhibit the glutamate-/glycine-evoked current and cytotoxic effects. However, the analogous phenols 16 c ((3-phenylpropyl)amino moiety) and 16 d ((4-phenylbutyl)amino moiety) with 10-fold lower GluN2B affinity (Ki =28 and 21 nm, respectively) showed promising inhibition of glutamate-/glycine-evoked effects in both assays. The presence of a phenolic hydroxy group seems to be essential for inducing conformational changes of the receptor protein, which finally results in closure of the ion conduction pathway.


Subject(s)
Benzocycloheptenes/pharmacology , Drug Design , Molecular Docking Simulation , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Benzocycloheptenes/chemical synthesis , Benzocycloheptenes/chemistry , Dose-Response Relationship, Radiation , Humans , Molecular Structure , Structure-Activity Relationship
7.
Free Radic Biol Med ; 106: 228-235, 2017 05.
Article in English | MEDLINE | ID: mdl-28223196

ABSTRACT

In this study, the mechanism of the xanthine oxidase (XO) inhibitory activity of pyrogallol, the main inhibitor found in roasted coffee, was investigated. Pyrogallol was unstable and readily converted to purpurogallin in a pH 7.4 solution, a physiological model of human body fluids. The XO inhibitory activity of the produced purpurogallin was higher than that of pyrogallol, as evidenced by comparing their IC50 values (0.2µmolL-1 for purpurogallin, 1.6µmolL-1 for pyrogallol). The XO activity of pyrogallol was enhanced by pre-incubation in pH 7.4 solution. Although the initial XO inhibitory activity of 4-methylpyrogallol was weak (IC50 33.3µmolL-1), its XO inhibitory activity was also enhanced by pre-incubation in the pH 7.4 solution. In contrast, 5-methylpyrogallol, which could not be transformed into corresponding purpurogallin derivatives, did not show XO inhibitory activity before or after incubation in pH 7.4 solution. Molecular docking simulations clarified that purpurogallins have stronger affinities for XO than corresponding pyrogallols. These results revealed that the potent XO inhibitory activity seemingly observed in pyrogallol is actually derived from its chemical conversion, under alkaline conditions, into purpurogallin.


Subject(s)
Benzocycloheptenes/chemistry , Pyrogallol/metabolism , Xanthine Oxidase/chemistry , Allopurinol , Benzocycloheptenes/metabolism , Coffee/chemistry , Humans , Molecular Docking Simulation , Oxidation-Reduction , Pyrogallol/chemistry , Xanthine Oxidase/antagonists & inhibitors
8.
J Med Chem ; 59(16): 7478-96, 2016 08 25.
Article in English | MEDLINE | ID: mdl-27527804

ABSTRACT

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.


Subject(s)
Benzamides/pharmacology , Benzocycloheptenes/pharmacology , Drug Discovery , Focal Adhesion Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Benzocycloheptenes/administration & dosage , Benzocycloheptenes/chemistry , Cell Line, Tumor , Cell Proliferation , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Focal Adhesion Kinase 1/metabolism , Humans , Mice , Mice, Nude , Mice, SCID , Models, Molecular , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship
9.
Bioorg Med Chem Lett ; 25(16): 3251-5, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26077488

ABSTRACT

Two series of novel 1,5-naphthyridine and 1,6-naphthyridine derivatives were designed and synthesized based on the c-Met kinase inhibitor MK-2461 under the guidance of scaffold hopping strategy. All were tested on c-Met kinase and in vitro anti-tumor activities against Hela and A549 cell lines. The results indicated that 1,6-naphthyridine was a more promising c-Met inhibitory structure core compared with 1,5-naphthyridine. Among them, 26b and 26c showed the best enzymic and cytotoxic activities. The western blot experiments implied that the cytotoxic activity of 26c might be partially through suppressing the phosphorylation of c-Met kinase.


Subject(s)
Benzocycloheptenes/pharmacology , Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzocycloheptenes/chemistry , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Drug Design , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Structure-Activity Relationship , X-Ray Diffraction
10.
Bioorg Med Chem ; 23(13): 3192-207, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25982416

ABSTRACT

In order to probe the S1 and S1' mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with Ki values in the nanomolar range.


Subject(s)
Aminobenzoates/chemical synthesis , Benzocycloheptenes/chemical synthesis , CD13 Antigens/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Aminobenzoates/chemistry , Animals , Benzocycloheptenes/chemistry , CD13 Antigens/chemistry , CD13 Antigens/isolation & purification , Kidney/chemistry , Kidney/enzymology , Molecular Docking Simulation , Molecular Structure , Protease Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship , Swine , Thermodynamics
11.
Bioorg Med Chem ; 22(23): 6638-6646, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-25458498

ABSTRACT

Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki=2.3nM and 2.9nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist.


Subject(s)
Benzocycloheptenes/chemical synthesis , Benzocycloheptenes/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Benzocycloheptenes/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Piperazines/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity Relationship
12.
Chem Pharm Bull (Tokyo) ; 62(3): 254-9, 2014.
Article in English | MEDLINE | ID: mdl-24583779

ABSTRACT

Selective ligands for retinoic acid receptors (RARs) and for retinoid X receptors (RXRs) are required for both biological studies and therapeutic purposes. We have synthesized a series of diarylamines incorporating hexahydrophenalene or octahydrobenzoheptalene as a hydrophobic moiety and examined their activities towards RARs and RXRs. Most of these compounds showed agonistic activity towards RXRs, but were inactive towards RARs. These RXR-specific ligands showed synergistic activity in RARα,ß ligand-induced terminal differentiation of leukemia cell line HL-60.


Subject(s)
Amines/chemistry , Amines/pharmacology , Phenalenes/chemistry , Phenalenes/pharmacology , Retinoid X Receptors/agonists , Amines/chemical synthesis , Animals , Benzocycloheptenes/chemistry , COS Cells , Cell Differentiation/drug effects , Chlorocebus aethiops , Drug Synergism , HL-60 Cells , Humans , Phenalenes/chemical synthesis , Structure-Activity Relationship
13.
ChemMedChem ; 9(4): 741-51, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24677663

ABSTRACT

Given their high neuroprotective potential, ligands that block GluN2B-containing N-methyl-D-aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B-selective NMDA receptor antagonists with the benzo[7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N-(2-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)acetamide (11), was obtained by cyclization of 3-acetamido-5-(3-methoxyphenyl)pentanoic acid (10 b). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis- and trans-configured 7-(ω-phenylalkylamino)benzo[7]annulen-5-ols. High GluN2B affinity was observed with cis-configured γ-amino alcohols substituted with a 3-phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2-methoxy-N-(3-phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine (20 a, Ki =10 nM) and 2-methoxy-N-methyl-N-(3-phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine (23 a, Ki =7.9 nM). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ1 and σ2 receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo[7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit-containing NMDA receptors was not inhibited by the new ligands.


Subject(s)
Benzazepines/pharmacology , Benzocycloheptenes/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Benzazepines/chemical synthesis , Benzazepines/chemistry , Benzocycloheptenes/chemical synthesis , Benzocycloheptenes/chemistry , Cells, Cultured , Crystallography, X-Ray , Dose-Response Relationship, Drug , Mice , Models, Molecular , Molecular Structure , Structure-Activity Relationship
14.
BMB Rep ; 47(7): 376-81, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24286332

ABSTRACT

Enzymatic oxidation of pyrogallol was efficiently transformed to an oxidative product, purpurogallin (PPG). Here, the anticoagulant activities of PPG were examined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). And, the effects of PPG on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor (TNF)-α activated human umbilical vein endothelial cells (HUVECs). Treatment with PPG resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, PPG inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. PPG also elicited anticoagulant effects in mice. In addition, treatment with PPG resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, PPG possesses antithrombotic activities and offers a basis for development of a novel anticoagulant.


Subject(s)
Anticoagulants/pharmacology , Benzocycloheptenes/pharmacology , Blood Platelets/drug effects , Platelet Aggregation Inhibitors/pharmacology , Animals , Anticoagulants/chemistry , Benzocycloheptenes/chemistry , Biological Transport/drug effects , Blood Platelets/metabolism , Cell Survival/drug effects , Cells, Cultured , Factor Xa/chemistry , Factor Xa/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Mice , Partial Thromboplastin Time , Plasminogen Activator Inhibitor 1/metabolism , Platelet Aggregation Inhibitors/chemistry , Thrombin/antagonists & inhibitors , Thrombin/metabolism , Tissue Plasminogen Activator/metabolism , Tumor Necrosis Factor-alpha/pharmacology
15.
Bioorg Med Chem ; 21(24): 8019-32, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24183586

ABSTRACT

Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 µM) and strongly cytotoxic against selected human cancer cell lines (for example, GI50=5.47 nM against NCI-H460 cells with fluoro-benzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study.


Subject(s)
Antineoplastic Agents/pharmacology , Benzocycloheptenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzocycloheptenes/chemical synthesis , Benzocycloheptenes/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Polymerization/drug effects , Structure-Activity Relationship , Tubulin/metabolism
16.
J Comput Aided Mol Des ; 27(10): 897-915, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24178966

ABSTRACT

Fragment-based drug design has emerged as an important methodology for lead discovery and drug design. Different with other studies focused on fragment library design and active fragment identification, a fragment-based strategy was developed in combination with three-dimensional quantitative structure-activity relationship (3D-QSAR) for structural optimization in this study. Based on a validated scaffold or fragment hit, a series of structural optimization was conducted to convert it to lead compounds, including 3D-QSAR modelling, active site analysis, fragment-based structural optimization and evaluation of new molecules. 3D-QSAR models and active site analysis provided sufficient information for confirming the SAR and pharmacophoric features for fragments. This strategy was evaluated through the structural optimization on a c-Met inhibitor scaffold 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one, which resulted in an c-Met inhibitor with high inhibitory activity. Our study suggested the effectiveness of this fragment-based strategy and the druggability of our newly explored active region. The reliability of this strategy indicated it could also be applied to facilitate lead optimization of other targets.


Subject(s)
Benzocycloheptenes/chemistry , Drug Design , Proto-Oncogene Proteins/antagonists & inhibitors , Pyridines/chemistry , Quantitative Structure-Activity Relationship , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Catalytic Domain , Humans , Models, Theoretical , Proto-Oncogene Proteins/chemistry , Receptor Protein-Tyrosine Kinases/chemistry , Structure-Activity Relationship , c-Mer Tyrosine Kinase
17.
J Med Chem ; 56(20): 8201-5, 2013 Oct 24.
Article in English | MEDLINE | ID: mdl-24053696

ABSTRACT

3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [(3)H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity, and we demonstrate in vivo brain penetration. In vitro characterization of [(3)H]-1 binding shows high specificity to the high-affinity GHB binding sites.


Subject(s)
Carboxylic Acids/metabolism , Central Nervous System/metabolism , Cyclopentanes/metabolism , Hydroxybutyrates/metabolism , Animals , Benzocycloheptenes/chemistry , Benzocycloheptenes/metabolism , Binding Sites , Binding, Competitive , Brain/metabolism , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Cell Line , Cyclopentanes/chemical synthesis , Cyclopentanes/chemistry , Drug Stability , Hydroxybutyrates/chemistry , Kinetics , Ligands , Male , Models, Chemical , Molecular Structure , Radioligand Assay , Rats , Rats, Sprague-Dawley , Synaptic Membranes/metabolism , Tritium/metabolism , gamma-Aminobutyric Acid/chemistry , gamma-Aminobutyric Acid/metabolism
18.
Bioorg Med Chem ; 21(21): 6447-55, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-24055078

ABSTRACT

Racemic trisubstituted benzocycloheptanes were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. A highly selective nanomolar inhibitor of a prototypical 'two zinc' aminopeptidase from the M28 family was observed with these tridentate species, while bidentate analogs proved to be highly selective for the 'one zinc' M1 family of enzymes. The selectivity profile of these new, low molecular weight structures may guide the design of specific, non-peptidic inhibitors of binuclear aminopeptidases.


Subject(s)
Aminopeptidases/antagonists & inhibitors , Benzocycloheptenes/chemistry , Protease Inhibitors/chemical synthesis , Aeromonas/enzymology , Aminopeptidases/metabolism , Benzocycloheptenes/chemical synthesis , Benzocycloheptenes/metabolism , Binding Sites , Catalytic Domain , Escherichia coli/enzymology , Molecular Docking Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protein Binding , Structure-Activity Relationship , Zinc/chemistry
19.
Yao Xue Xue Bao ; 48(3): 315-24, 2013 Mar.
Article in Chinese | MEDLINE | ID: mdl-23724641

ABSTRACT

Polo-box domain 1 (PBD1) is a characteristic domain of polo-like kinase 1 (PLK1), which locates in C-terminal and can influence the catalytic activity and specific subcellular locations of PLK1. At present, most PLK1 inhibitors are developed to occupy the ATP pocket or its close sites. However, this kind of PLK1 inhibitors is difficult to pursue target selectivity and may encounter cross drug resistance with other kinase inhibitors due to the conserved sequence of ATP pocket. Recently, PBD1, with aberrant specificity in sequence and structure, has attracted enormous interests as the alternative target to the discovery of corresponding inhibitors for anti-tumor drugs. The structure and function of PBD1 as well as the advances of its inhibitors are reviewed in this paper.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Benzocycloheptenes/chemistry , Benzocycloheptenes/pharmacology , Benzoquinones/chemistry , Benzoquinones/pharmacology , Cell Cycle Proteins/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indole Alkaloids/chemistry , Indole Alkaloids/pharmacology , Lactams/chemistry , Lactams/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Phosphopeptides/chemistry , Phosphopeptides/pharmacology , Protein Serine-Threonine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Polo-Like Kinase 1
20.
J Med Chem ; 56(6): 2294-310, 2013 Mar 28.
Article in English | MEDLINE | ID: mdl-23379595

ABSTRACT

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.


Subject(s)
Benzocycloheptenes/metabolism , Benzocycloheptenes/pharmacology , Drug Discovery , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Sulfonamides/metabolism , Sulfonamides/pharmacology , Animals , Benzocycloheptenes/chemistry , Cell Line, Tumor , Dogs , Enzyme Activation/drug effects , Female , Humans , Mice , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/chemistry , Rats , Substrate Specificity , Sulfonamides/chemistry , Xenograft Model Antitumor Assays
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