Human papillomavirus and p53 oncoprotein in verrucous carcinoma of the larynx

An in vitro screening method for selective acetylcholinesterase (AChE) inhibitors was established. Inhibitory activity of AChE and butyrylcholinesterase (BuChE) was measured and the culture broths of microorganisms that showed selective inhibition against AChE were characterized. By using this method, a strain producing the novel and selective inhibitors of AChE, arisugacins A and B, was picked out among over seven thousand microorganisms tested. Arisugacins were obtained as white powders from the culture broth together with three known compounds, territrems B and C and cyclopenin that also showed selective inhibition against AChE. Arisugacins and territrems are members of the meroterpenoid compounds. They showed potent inhibitory activities against AChE with IC50 values in range of 1.0 approximately 25.8 nM. Furthermore, they showed greater than 2,000-fold more potent inhibition against AChE than BuChE.     

Inhibition of human cytomegalovirus protease N(o) with monocyclic beta-lactams

Monocyclic beta-lactams have been identified as potent and selective inhibitors of the human cytomegalovirus protease (HCMV) N(o). Two series of these inhibitors are described, a peptidyl series of compounds and non-peptidic molecules featuring lower molecular weights. The SAR work that lead to the discovery of these inhibitors, together with their synthesis is also disclosed.     

Potent and selective thrombin inhibitors featuring hydrophobic, basic P3-P4-aminoalkyllactam moieties

Crystal structure and evolving SAR considerations of potent, selective benzylsulfonamide lactam thrombin inhibitors and related serine protease inhibitors have led to the design of novel thrombin inhibitors 1a-g, featuring hydrophobic, basic, P4-alkylaminolactam scaffolds that serve as novel types of P3-P4 dipeptide mimics. The design, synthesis, and biological activity of these targets is presented.     

Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library

An encoded 13,020-member combinatorial library was synthesized containing a statine core. Evaluation of this library with plasmepsin II, an aspartyl protease required for hemoglobin metabolism in the malaria parasite, led to the identification of potent and selective inhibitors as well as novel structure-activity relationships.     

Synthesis and evaluation of a novel series of phosphodiesterase IV inhibitors. A potential treatment for asthma

The synthesis and pharmacological profile of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors is described.     

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

Proteasome inhibitors: valuable new tools for cell biologists

Proteasomes are major sites for protein degradation in eukaryotic cells. The recent identification of selective proteasome inhibitors has allowed a definition of the roles of the ubiquitin-proteasome pathway in various cellular processes, such as antigen presentation and the degradation of regulatory or membrane proteins. This review describes the actions of these inhibitors, how they can be used to investigate cellular responses, the functions of the proteasome demonstrated by such studies and their potential applications in the future.     

Highly efficient and versatile synthesis of libraries of constrained beta-strand mimetics

The general approach of using a bicyclic template to produce inhibitors of the protease superfamily of enzymes has been investigated. The Diels Alder cycloaddition reaction on solid support has been found to be highly efficient for the synthesis of libraries of compounds that mimic the beta-strand secondary structure of proteins. Several potent and selective inhibitors of proteases have been discovered.     

Dicaffeoylquinic acid inhibitors of human immunodeficiency virus integrase: inhibition of the core catalytic domain of human immunodeficiency virus integrase

Integration of a cDNA copy of the human immunodeficiency virus (HIV) genome is mediated by an HIV-1-encoded enzyme, integrase (IN), and is required for productive infection of CD4+ lymphocytes. It had been shown that 3,5-dicaffeoylquinic acid and two analogues were potent and selective inhibitors of HIV-1 IN in vitro. To determine whether the inhibition of IN by dicaffeoylquinic acids was limited to the 3,5 substitution, 3,4-, 4,5-, and 1,5-dicaffeoylquinic acids were tested for inhibition of HIV-1 replication in tissue culture and inhibition of HIV-1 IN in vitro. All of the dicaffeoylquinic acids were found to inhibit HIV-1 replication at concentrations ranging from 1 to 6 microM in T cell lines, whereas their toxic concentrations in the same cell lines were > 120 microM. In addition, the compounds inhibited HIV-1 IN in vitro at submicromolar concentrations. Molecular modeling of these ligands with the core catalytic domain of IN indicated an energetically favorable reaction, with the most potent inhibitors filling a groove within the predicted catalytic site of IN. The calculated change in internal free energy of the ligand/IN complex correlated with the ability of the compounds to inhibit HIV-1 IN in vitro. These results indicate that the dicaffeoylquinic acids as a class are potent and selective inhibitors of HIV-1 IN and form important lead compounds for HIV drug discovery.     

The de novo design and synthesis of cyclic urea inhibitors of factor Xa: initial SAR studies

In this report we discuss the design, synthesis, and validation of a novel series of cyclic urea inhibitors of the blood coagulation protein Factor Xa. This work culminates in compound 11, a monoamidine inhibitor of fXa employing a new S4 ligand that reduces the cationic character of these analogs. Compound 11 represents a lead for a series of more potent and selective inhibitors.     

Paeciloquinones A, B, C, D, E and F: new potent inhibitors of protein tyrosine kinases produced by Paecilomyces carneus. I. Taxonomy, fermentation, isolation and biological activity

Paeciloquinones A to F as well as versiconol have been isolated as inhibitors of protein tyrosine kinase from the culture broth of the fungus Paecilomyces carneus P-177. The novel anthraquinones inhibit epidermal growth factor receptor protein tyrosine kinase in the micromolar range. Two compounds, paeciloquinones A and C, are potent and selective inhibitors of the v-abl protein tyrosine kinase with an IC50 of 0.4 microM. Dependent on the fermentation conditions, partially different sets of paeciloquinones may be produced. An HPLC method allows separation of all major active components.     

Seven-day treatment for Helicobacter pylori infection: ranitidine bismuth citrate plus clarithromycin and tetracycline hydrochloride

1. We have examined a series of novel phosphinic peptides as putative potent and selective inhibitors of endopeptidase 3.4.24.16. 2. The most selective inhibitor, Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 displayed a Ki value of 12 nM towards endopeptidase 3.4.24.16 and was 5540 fold less potent on its related peptidase endopeptidase 3.4.24.15. Furthermore, this inhibitor was 12.5 less potent on angiotensin-converting enzyme and was unable to block endopeptidase 3.4.24.11, aminopeptidases B and M, dipeptidylaminopeptidase IV and proline endopeptidase. 3. The effect of Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2, in vitro and in vivo, on neurotensin metabolism in the central nervous system was examined. 4. Pro-Phe-psi(PO2CHH2)-Leu-Pro-NH2 dose-dependently inhibited the formation of neurotensin 1-10 and concomittantly protected neurotensin from degradation by primary cultured neurones from mouse embryos. 5. Intracerebroventricular administration of Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 significantly potentiated the neurotensin-induced antinociception of mice in the hot plate test. 6. Altogether, our study has established Pro-Phe-psi(PO2CH2)-Leu-Pro-NH2 as a fully selective and highly potent inhibitor of endopeptidase 3.4.24.16 and demonstrates, for the first time, the contribution of this enzyme in the central metabolism of neurotensin.     

2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase

A series of substituted 2-iminopyrrolidines has been prepared and shown to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxide synthase (heNOS) and the human neuronal nitric oxide synthase (hnNOS). Simple substitutions at the 3-, 4-, or 5-position afforded more potent analogues than the parent 2-iminopyrrolidine 1. The effect of ring substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2-iminopyrrolidine yielded both potent and selective inhibitors of hiNOS. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohydrochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 microM) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50/hiNOS IC50). Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressure at multiples of the effective dose in the mouse.     

Metallopeptidase inhibitors of tetanus toxin: A combinatorial approach

The bacterial protein tetanus toxin (TeNt), which belongs to the family of zinc endopeptidases, cleaves synaptobrevin, an essential synaptic protein component of the neurotransmitter exocytosis apparatus, at a single peptide bond (Gln76-Phe77). This protease activity is a particularly attractive target for designing potent and selective synthetic inhibitors as a possible drug therapy for tetanus. beta-Aminothiols mimicking Gln76 of synaptobrevin have been previously shown to inhibit the tetanus neurotoxin enzymatic activity in the 35-250 microM range. These compounds have now been modified to interact with S' subsites of the TeNt active site, with the aim of increasing their inhibitory potencies. Combinatorial libraries of pseudotripeptides, containing an ethylene sulfonamide or an m-sulfonamidophenyl moiety as the P1 side chain and natural amino acids in P1' and P2' positions, were synthesized. The best inhibitory activity was observed with Tyr and His as P1' and P2' components, respectively. This led to new inhibitors of TeNt with Ki values in the 3-4 microM range. These molecules are the most potent inhibitors of TeNt described so far.     

Tomoxiprole selectively inhibits cyclooxygenase-2

Tomoxiprole is a nonsteroidal anti-inflammatory compound that was reported to have low ulcerogenic potential, a quality that would be expected of a cyclooxygenase-2-selective inhibitor, and, in fact, we find it is selective for this isozyme. In stably transfected COS cells, the compound inhibits recombinant human cyclooxygenase-2 (IC50 = 7 nM) more potently than recombinant cyclooxygenase-1 (IC50 = 240 nM), and similar results are obtained with partially pure ovine enzyme preparations. The compound is thus a very potent as well as selective inhibitor of cyclooxygenase-2. As is true of some other cyclooxygenase-2-selective inhibitors, tomoxiprole inhibition of cyclooxygenase-2 but not cyclooxygenase-1 is time-dependent.     

Actinoplanic acids A and B as novel inhibitors of farnesyl-protein transferase

Actinoplanic acids A and B are macrocyclic polycarboxylic acids that are potent reversible inhibitors of farnesyl-protein transferase. Actinoplanic acids A and B were isolated from Actinoplanes sp. MA 7066 while actinoplanic acid B was isolated from both MA 7066 and Streptomyces sp. MA 7099. Actinoplanic acids A and B are competitive with respect to farnesyl diphosphate and are selective inhibitors of farnesyl-protein transferase because they do not inhibit geranylgeranyl-protein transferase type 1 or squalene synthase. MA 7066 is believed to be a novel species of actinomycetes while MA 7099 is believed to be a novel strain of Streptomyces violaceusniger on the basis of morphological, biochemical and chemotaxonomic characteristics as well as its production of actinoplanic acids.     

Involvement and dual effects of nitric oxide in septic shock

Bacterial endotoxin (LPS) releases many mediators such as interleukins, tumour necrosis factor, oxygen free radicals, toxic eicosanoids, platelet activating factor, and nitric oxide (NO). LPS is a potent inducer of inducible nitric oxide synthase (iNOS). Large amounts of NO (made by iNOS) and peroxynitrite, among other factors, are responsible for the late phase of hypotension, vasoplegia, cellular suffocation, apoptosis, lactic acidosis and multiorgan failure in endotoxic shock. Indeed, experimental and clinical use of NOS inhibitors, which do not differentiate clearly between constitutive endothelial NOS (ceNOS) and iNOS, prevents LPS-induced hypotension. However, many detrimental effects of such NOS inhibitors are also reported, including increases in pulmonary resistance, decreases in cardiac output and organ perfusion, and even an increase in mortality of experimental animals. We believe that, in lungs, NO made by ceNOS plays a protective role against the pneumotoxic effects of LPS-released lipids such as thromboxane, leukotrienes and PAF. This is why selective iNOS inhibitors like aminoguanidine or thiourea derivatives might be preferred over nonselective NOS inhibitors for the treatment of septic shock. However, since iNOS-derived NO seems to have more than just a destructive action, the selective iNOS inhibition may be not as beneficial as expected. Accordingly, inhalation of NO gas or NO-donors in septic shock might be a complementary treatment to the use of NOS inhibitors.     

Inhibition and inactivation of murine hepatic ethoxy- and pentoxyresorufin O-dealkylase by naturally occurring coumarins

The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.     

Antiinflammatory 2-benzyl-4-sulfonyl-4H-isoquinoline-1,3-diones: novel inhibitors of COX-2

A series of 2-benzyl-4-sulfonyl-4H-isoquinoline-1,3-diones was prepared. Members of this series are potent and selective inhibitors of cyclooxygenase-2 (COX-2) in both microsomal and cellular assays. Two representatives demonstrated activity in the carrageenan-induced paw edema model in rats upon oral administration.     

Structural modification of an orally active thrombin inhibitor, LB30057: replacement of the D-pocket-binding naphthyl moiety

An amidrazonophenylalanine derivative LB30057 (2) was identified as a potent (Ki = 0.38 nM), selective, and orally active thrombin inhibitor. As a continuation of studies into benzamidrazone-based thrombin inhibitors, we have structurally modified compound 2 by replacing the naphthyl group with a variety of hydrophobic moieties. This study led to discovery of several compounds with significantly enhanced potency in thrombin inhibition without sacrificing selectivity against trypsin and oral absorption. The highest activity was obtained with compound 23 (Ki = 0.045 nM).