Quinoxalinylethylpyridylthioureas (QXPTs) as potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Further SAR studies and identification of a novel orally bioavailable hydrazine-based antiviral agent.

Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro.

Isolation and characterization of an acute promyelocytic leukemia cell line selectively resistant to the novel antileukemic and apoptogenic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid.

6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) is a novel compound that represents the prototype of a new class of synthetic retinoids with apoptogenic properties in acute promyelocytic leukemia (APL) and other types of leukemia. In this article, using SCID mice xenografted with APL-derived NB4 cells, we demonstrate that CD437 has significant antileukemic activity in vivo. In addition, we report on the isolation and characterization of an APL cell line (NB4.

Inhibition of matrix metalloproteinases by over-expression of tissue inhibitor of metalloproteinase-2 inhibits the growth of experimental hemangiomas.

Inhibitors of proteases prevent tumor-associated matrix degradation, affecting tumor growth, angiogenesis and metastasis. Our study was designed to investigate the effect of inhibition of matrix metalloproteinases (MMPs) on the growth of experimental hemangiomas, using the model of murine endothelioma eEnd.1 cells.

Syngeneic murine metastasis models : b16 melanoma.

Animal studies are costly, time consuming, and subject to several restrictive regulations. However, the metastatic process is one of the research areas in which the in vivo studies remain most relevant (1). In fact, the in vitro studies are not fully predictive of the metastatic behavior of a tumor cell, probably because in vitro, it is difficult to reproduce the complexity of the metastatic process in itself and the interaction with the host.

Thiazolothiazepine inhibitors of HIV-1 integrase.

A series of thiazolothiazepines were prepared and tested against purified human immunodeficiency virus type-1 integrase (HIV-1 IN) and viral replication. Structure-activity studies reveal that the compounds possessing the pentatomic moiety SC(O)CNC(O) with two carbonyl groups are in general more potent against purified IN than those containing only one carbonyl group. Substitution with electron-donating or -withdrawing groups did not enhance nor abolish potency against purified IN.

Diagnostic and prognostic value of peritoneal immunocytology in gastric cancer.

Purpose: Among the clinical factors with a pivotal role in the prediction of outcome for patients with gastric cancer, intraperitoneal (i.p.) microscopic dissemination may represent an important cause of recurrences, even in the early stages of the disease.

New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure.

The development of a synthetic approach to the novel pyrrolo[2, 1-b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (+/-)-3b was resolved into its enantiomers by using HPLC techniques.

Gastric cancer. Clinico-biological updating and analysis of 400 operated cases.

Gastric cancer is a rather common disease worldwide. In Italy it still accounts for 15,000 deaths annually. A sharp drop in the incidence rate of Lauren's intestinal histotype has been reported, whereas the frequency of the diffuse histotype is relatively steady.

Antihyperglycemic activities of cryptolepine analogues: an ethnobotanical lead structure isolated from Cryptolepis sanguinolenta.

Cryptolepine (1) is a rare example of a natural product whose synthesis was reported prior to its isolation from nature. In the previous paper we reported the discovery of cryptolepine's antihyperglycemic properties. As part of a medicinal chemistry program designed to optimize natural product lead structures originating from our ethnobotanical and ethnomedical field research, a series of substituted and heterosubstituted cryptolepine analogues was synthesized.

Batimastat, a synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts.

Batimastat (also known as BB-94) is a synthetic matrix metalloproteinase inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models. In this study, two human ovarian carcinoma (HOC) xenografts (HOC22 and HOC8) were used to investigate the effect of batimastat on the antineoplastic activity of cisplatin. Both xenografts produced ascites and solid lesions in the peritoneal cavity of nude mice.

Antiproliferative action of pyrrolobenzoxazepine derivatives in cultured cells: absence of correlation with binding to the peripheral-type benzodiazepine binding site.

Three novel peripheral-type benzodiazepine binding site (PBBS) ligands, NF 182, 213 and 262, along with the classically used PBBS ligands, PK 11195 and Ro5-4864, were found to inhibit, at micromolar concentrations and in dose-dependent manner, the proliferation of rat C6 glioma and human 1321N1 astrocytoma, without being cytotoxic. This antiproliferative effect is mediated by arrest in the G1 phase of the cell cycle and does not appear to be mediated by a specific interaction of these ligands with the peripheral-type benzodiazepine binding site.

A human acute lymphoblastic leukemia line with the T(4;11) translocation as a model of minimal residual disease in SCID mice.

This study describes a new human acute lymphoblastic leukemia (ALL) cell line (ALL-PO) with the t(4;11) translocation established in SCID mice. The ALL-PO line can be maintained by serial transplant in SCID mice with stable immunophenotypic, molecular and karyotypic features. After intravenous (i.

DNA ploidy, proliferative index and EGF-R status in 130 cases of resected gastric cancer--a multivariate analysis.

Background/aims: The purpose of this study was to define the prognostic role of DNA ploidy, proliferative index and EGF-R status in resected gastric cancer.

Materials And Methods: Ten clinico-pathological parameters and three biological factors obtained from flow cytometry and immunohisto-chemistry were evaluated in a series of 130 gastric cancer patients who received surgical treatment, including 28 stage IV cases (21.6%), using paraffin-embedded and fresh specimens in 77.

Increase in beta-galactosidase activity in a non-isothermal bioreactor utilizing immobilized cells of Kluyveromyces fragilis: fundamentals and applications.

The beta-galactosidase activity of Kluyveromyces fragilis cells immobilized in a kappa carrageenan gel was studied in a bioreactor functioning under isothermal and non-isothermal conditions. We observed an increase in enzyme activity which was found to be proportional to the intensity of the temperature gradient applied across the biocatalytic membrane, as well as to the average temperature of the bioreactor. The efficiency of such a non-isothermal bioreactor was calculated with respect to the yield of a bioreactor working under comparable isothermal conditions and was evaluated in terms of reduction of processing times in industrial applications.

Synthesis of Chiral alpha,delta-Dioxygenated Allylic Stannanes as Reagents for Carbohydrate Synthesis and Homologation.

The delta-oxygenated allylic stannanes 4.4 and 4.5, prepared through addition of Bu(3)SnLi to gamma-OTBS crotonaldehyde 4.

IL-1alpha gene-transfected human melanoma cells increase tumor-cell adhesion to endothelial cells and their retention in the lung of nude mice.

The interleukin-1alpha(IL-1) gene was introduced by retroviral gene transfer into the A375P human melanoma cell line. Two hygromycin-resistant colonies, colony 3 and colony 6, which respectively do not and do express and release IL-1, were selected on the basis of Northern blot and ELISA. Both colonies adhered to resting human endothelial cells (EC) to the same extent.

Synthesis, biological activity, and SARs of pyrrolobenzoxazepine derivatives, a new class of specific "peripheral-type" benzodiazepine receptor ligands.

The "peripheral-type" benzodiazepine receptor (PBR) has been reported to play a role in many biological processes. We have synthesized and tested a novel series of PBR ligands based on a pyrrolobenzoxazepine skeleton, in order to provide new receptor ligands. Several of these new compounds proved to be high affinity and selective ligands for PBR, and benzoxazepines 17f and 17j were found to be the most potent ligands for this receptor to have been identified to date.

Cardiovascular characterization of pyrrolo[2,1-d][1,5]benzothiazepine derivatives binding selectively to the peripheral-type benzodiazepine receptor (PBR): from dual PBR affinity and calcium antagonist activity to novel and selective calcium entry blockers.

The synthesis and cardiovascular characterization of a series of novel pyrrolo[2,1-d][1,5]-benzothiazepine derivatives (54-68) are described. Selective peripheral-type benzodiazepine receptor (PBR) ligands, such as PK 11195 and Ro 5-4864, have recently been found to possess low but significant inhibitory activity of L-type calcium channels, and this property is implicated in the cardiovascular effects observed with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue.

Pyrrolobenzothiazepinones and pyrrolobenzoxazepinones: novel and specific non-nucleoside HIV-1 reverse transcriptase inhibitors with antiviral activity.

Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calfthymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring.

Erythrocyte enzymes catalyze 1-nitropyrene and 3-nitrofluoranthene nitroreduction.

Nitroarenes are environmental contaminants produced during incomplete combustion processes. Nitroreduction, the most important pathway of nitroarene toxification, occurs mainly in the liver and intestine. In the present study, we show that human red cells may also possess the metabolic competence to reduce 1-nitropyrene (NP) and 3-nitrofluoranthene (NF), the nitroarenes chosen as model compounds, to their corresponding amino derivatives, 1-aminopyrene (AP) and 3-aminofluoranthene (AF).

A non-isothermal bioreactor utilizing immobilized baker's-yeast cells: a study of the effect on invertase activity.

The behaviour of the enzyme invertase, located on the cell wall of baker's-yeast cells and entrapped in a gelatin membrane, was studied under isothermal and non-isothermal conditions. The reaction rate linearly increased with the applied transmembrane temperature gradient, with reference either to the average temperature or to the temperature on the warm side of the catalytic membrane. These results were obtained both when the bioreactor was operated under conditions of closed volumes and when the substrate-containing solutions are recirculated.

Pyrrolo[2,1-c][1,4]benzothiazines: synthesis, structure-activity relationships, molecular modeling studies, and cardiovascular activity.

The synthesis and pharmacological evaluation of a series of pyrrolo[1,4]benzothiazine derivatives are described. These compounds, related to diltiazem, have been shown to be representative of a novel series of calcium channel antagonists. The IC50S for inhibition of [3H]nitrendipine binding calculated by radioreceptor assay on rat cortex and rat heart homogenates showed that some of the described compounds possess an affinity equal to or higher than those of the reference calcium antagonists verapamil and cis-(+)-diltiazem.

Establishment of human acute myelogenous leukemia lines secreting interleukin-1 beta in SCID mice.

A reproducible in vivo model of human acute myelogenous leukemia (AML) was established in severe combined immunodeficient (SCID) mice. The AML-CL and AML-PS lines were originated from leukemic blasts purified respectively from the peripheral blood of a 27-year-old woman with previously untreated hyperleukocytotic AML and from the bone marrow of a 61-year-old man during the third leukemic relapse. The 2 lines were maintained and serially transplanted i.

DNA ploidy, proliferative index, and epidermal growth factor receptor: expression and prognosis in patients with gastric cancers.

Background: The 5-year survival rate of patients with stomach cancer is usually around 20%. The clinico-pathological features that are presently used to assess patient prognosis are not sufficient to define gastric tumor behavior. Therefore, an accurate analysis of different biological characteristics of gastric cancer cells could allow the course of disease to be predicted and may help to improve treatment strategies.

Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases.

Background: The importance of matrix metalloproteinases in angiogenesis, tumor growth, and metastasis is well known. However, little is known about the role of matrix metalloproteinases in the formation of hemangiomas and about the possible therapeutic use of matrix metalloproteinase inhibitors in aggressive vascular tumors.

Purpose: To study the role of matrix metalloproteinase in vascular tumors, we tested the antineoplastic activity of a synthetic inhibitor of matrix metalloproteinases, batimastat, on an experimental model of hemangioma, formed by murine endothelioma cells transformed by polyoma middle-T oncogene (eEnd.