51-75-2

New oxorhenium complexes with tridentate 3-thia- and 3-methylazapentane-1, 5-dithiolate and monodentate pyridine and quinoline derivatives have been synthesized. As a result of investigation of biological activity a high cytotoxicity was found for the synthesized complexes in relation to tumor cells. The specificity of the 2-pyridylthiolato[3-(N-methyl)azapentane-1,5-dithiolato] oxorhenium(V) cytotoxic action towards cells of mouse hepatoma MG-22A on a background of low acute toxicity was established.

Amide bonds are ubiquitous in peptides, proteins, pharmaceuticals, and polymers. The formation of amide bonds is a straightforward process: amide bonds can be synthesized with relative ease because of the availability of efficient coupling agents. However, there is a substantive need for methods that do not require excess reagents. A catalyst that condenses amino acids could have an important impact by reducing the significant waste generated during peptide synthesis. We describe the rational design of a biomimetic catalyst that can efficiently couple amino acids featuring standard protecting groups. The catalyst design combines lessons learned from enzymes, peptide biosynthesis, and organocatalysts. Under optimized conditions, 5 mol % catalyst efficiently couples Fmoc amino acids without notable racemization. Importantly, we demonstrate that the catalyst is functional for the synthesis of oligopeptides on solid phase. This result is significant because it illustrates the potential of the catalyst to function on a substrate with a multitude of amide bonds, which may be expected to inhibit a hydrogen-bonding catalyst.

Two series of closely related SNS pincer ligands (L) were synthesised with the major structural variation on the nitrogen backbone containing either the methyl [L = (RSCH2CH2)2NMe: where R = Me (1), Et (2), Bu (3)] or the phenyl [L = (RSCH2CH2)2NPh: where R = Me (4), Et (5), Cy (6)] functional group. When ligands 1–3 were complexed to Ni by reaction with Ni(DME)Cl2 (DME = dimethoxyethane), they respectively yielded three new cationic dimeric [LNi(μ-Cl)3NiL]+ complexes (7–9), whilst ligands 4–6 on reaction with Ni(PPh3)2Br2 respectively yielded neutral mononuclear (LNiBr2) complexes 10–12. All the new compounds were characterised by IR, HRMS, elemental analysis and in addition, single crystal X-ray diffraction for complexes 9–12. X-ray structural data of 9 revealed an unusual three chlorido-bridged Ni dimer with the SNS ligand coordinated in a facial binding mode to the two pseudo-octahedral Ni centres. Molecular structures of complexes 10, 11 and 12 each displayed five-coordinate distorted trigonal bipyramidal geometry around the nickel(II) metal centres. When utilised as catalysts in the tert-butyl hydroperoxide oxidation of n-octane, all the complexes showed activity to mainly products of internal carbon activation (octanones and secondary octanols) with 11 as the most active (10% total substrate to oxygenates yield), whereas 10 was the least active, but most selective towards alcohols (alcohol/ketone = 2.13).

Disclosed are compounds having the formula: wherein X1, X2, X3, R1, R2, R3, R4, Y, A, Z, L and n are as defined herein, and methods of making and using the same.

A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.

The present invention relates to specific binding members, particularly antibodies and fragments thereof, which bind to amplified epidermal growth factor receptor (EGFR) and to the de2-7 EGFR truncation of the EGFR. In particular, the epitope recognized by the specific binding members, particularly antibodies and fragments thereof, is enhanced or evident upon aberrant post-translational modification. These specific binding members are useful in the diagnosis and treatment of cancer. The binding members of the present invention may also be used in therapy in combination with chemotherapeutics or anti-cancer agents and/or with other antibodies or fragments thereof.

The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anticancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs toward ROS was determined by measuring DNA interstrand cross-links and/or DNA alkylations. These compounds showed 60-90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H 2O2-activated anticancer prodrugs.

Sixteen novel cationic click polymers (CPs) were parallelly synthesized via the conjugation of four alkyne- functionalized monomers to four azide-functionalized monomers by "click chemistry". The biocompatibility of CPs was evaluated by in vitro cytotoxicity (MTT assay, Hoechst/PI apoptosis/necrosis assay, and cell cycle analysis) and blood compatibility tests (hemolysis and erythrocyte aggregation). The experimental results showed that the kind of amine groups, charge density, and number of methylene or ethylene glycol groups brought about the effect on toxicity of CPs. Among all polymers, two polymers (B1 and B2) showed good biocompatibility, inducing neither apoptosis nor necrosis at the test concentration and low hemolysis ratio and erythrocyte aggregation. In particular, B1 and B2 exhibited the comparable transfection efficiency compared with PEI (25 kDa) but much lower cytotoxicity. These results suggested that the novel cationic CPs could be promising carriers for gene delivery.

Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.

A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in markedly improved antiviral activity toward EV71 with IC50 values of 5.0 nM (24b) and 9.3 nM (14a), respectively. Increasing the branched chain to propyl resulted in a progressive decrease in activity, while inserting different heteroatoms entirely rendered the compound only weakly active. The introduction of a bulky group (cyclohexyl, phenyl, or benzyl) led to loss of activity against EV71. The 4-chlorophenyl moiety in 14a was replaced with bioisosteric groups such as oxadiazole (28a-d) or tetrazole (32a,b), dramatically improving anti-EV71 activity and selectivity indices. Compounds 14a, 24b, 28b, 28d, and 32a exhibited a strong activity against lethal EV71, and no apparent cellular toxicity was observed. Three of the more potent imidazolidinone compounds, 14a, 28b, and 32b, were subjected to a large group of picornaviruses to determine their spectrum of antiviral activity.

A therapeutic agent for myeloma comprising a combined use of a nitrogen mustard anticancer agent and anti-IL-6 receptor antibody. Thus, a therapeutic agent for myeloma comprising anti-IL-6 receptor antibody for use in combination with a nitrogen mustard anticancer agent; a therapeutic agent for myeloma comprising a nitrogen mustard anticancer agent for use in combination with anti-IL-6 receptor antibody; and a therapeutic agent for myeloma comprising a nitrogen mustard anticancer agent and anti-IL-6 receptor antibody.

The present invention is directed to low molecular weight mimics of superoxide dismutase (SOD) represented by the formula: STR1 wherein R, R', R1, R'1, R2, R'2, R3, R'3, R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9, and R'9 and X, Y, Z and n are as defined herein, useful as therapeutic agents for inflammatory disease states and disorders, ischemic/reperfusion injury, stroke, atherosclerosis, hypertension and all other conditions of oxidant-induced tissue damage or injury.

The present invention is directed to low molecular weight mimics of superoxide dismutase (SOD) represented by the formula: STR1 wherein R, R', R1, R'1, R2, R'2, R3, R'3, R4, R'4, R5, R'5, R6, R'6, R7, R'7, R8, R'8, R9, and R'9 and X, Y, Z and n are as defined herein, useful as therapeutic agents for inflammatory disease states and disorders, ischemic/reperfusion injury, stroke, atherosclerosis, hypertension and all other conditions of oxidant-induced tissue damage or injury.

Novel glycosylated steroid derivatives for facilitating the transport of compounds across biological membranes are disclosed. A novel process for efficient synthesis of these glycosylated steroid derivatives, using activated glycosyl sulfoxide intermediates is also provided.

A method for the treatment of emesis in a mammal, which method comprises administering to said mammal an emesis inhibiting amount of a compound which depletes serotonin in the brain of mammals; among which are compounds having the formula: STR1 wherein, R is selected from hydrogen, loweralkyl, trifluoromethyl, carboxyl, or loweralkoxycarbonyl; R1 and R2 are hydrogen or loweralkyl; Z is trifluoromethyl or halogen; the optical isomers and pharmaceutically acceptable salts thereof; two of the preferred compounds of the invention are fenfluramine and norfenfluramine.

New 4-(phenyl)-piperidine compounds of the general formula I STR1 in which R1 represents hydrogen or lower alkyl, Ph represents a p-phenylene group optionally substituted by lower alkyl, lower alkoxy, nitro and/or halogen, and R2 represents lower alkyl, and pharmaceutically acceptable acid addition salts thereof are useful as antidepressant agents.