ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.

Phase II trial of weekly gemcitabine and split-dose cisplatin for advanced non-small-cell lung cancer.

OBJECTIVE: Cisplatin is widely used for the treatment of non-small-cell lung cancer. However, it can cause unpleasant side effects and also requires prolonged hydration. We conducted a Phase II study of weekly gemcitabine and split-dose cisplatin in patients with advanced non-small-cell lung cancer (NSCLC) in order to reduce toxicity and shorten the time taken by administration. Our aims were to determine the response rate, toxicity and survival time with this regimen in patients with Stage IIIB/IV disease. METHODS: Previously untreated patients with Stage IIIB/IV NSCLC were given gemcitabine (1000 mg/m(2)) and split-dose cisplatin (40 mg/m(2)) on days 1 and 8 at 3-week intervals for four cycles. Gemcitabine was administered over the course of 30 min, and cisplatin was over the course of 60 min on the same days on an outpatient basis. RESULTS: Forty-five patients were enrolled, and all of them were assessable for response and toxicity. None had a complete response and 17 had a partial response (37.8%), for an overall response rate of 37.8% (95% confidence interval, 25.1-52.4%). The survival rate was 56.5% at 1 year and 38.9% at 2 years, with a median survival time of 15.7 months. Leukopenia, neutropenia, anemia and thrombocytopenia were the most common toxic reactions, with Grade > or = 3 reactions occurring at rates of 35%, 51%, 31% and 13%, respectively. CONCLUSIONS: Weekly gemcitabine and split-dose cisplatin is active and well tolerated in patients with Stage IIIB/IV NSCLC, administered on an outpatient basis without requiring prolonged hydration or hospitalization.

Effect of inducible nitric oxide synthase on apoptosis in Candida-induced acute lung injury.

Excessive nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) aggravates acute lung injury (ALI) by producing peroxinitrite. We previously showed that the expression of iNOS and lung injury were suppressed by inhalation of a novel iNOS inhibitor, ONO-1714, in mice with Candida-induced ALI, and that nitric oxide produced by iNOS and apoptosis of epithelial cells were found to have a crucial role in Candida-induced ALI. In the present study, we investigated the effect of NO on the apoptosis of alveolar epithelial cells in Candida-induced ALI. Mice were pretreated by inhalation of ONO-1714 or saline (vehicle control of ONO-1714), and were given an intravenous injection of Candida albicans to induce ALI. After 24 h from injection of Candida albicans, we performed bronchoalveolar lavage and removed lung tissues. We assessed apoptosis on the basis of TUNEL staining and caspase 3 activity. Our results showed that apoptosis was suppressed by inhibition of iNOS-derived NO production by ONO-1714 inhalation. The augmented production of NO increased FasL, TNF-alpha, and mRNA production of Bax of lung that induced apoptosis of alveolar epithelial cells. Inhibition of iNOS-derived NO production by ONO-1714 inhalation ameliorated Candida-induced ALI and improved survival by suppressing apoptosis of alveolar epithelial cells.

Structure-activity relationships study of bastadin 6, an anti-angiogenic brominated-tyrosine derived metabolite from marine sponge.

A structure-activity relationship (SAR) study of bastadin 6 (1), a brominated tyrosine-derived metabolite from Indonesian marine sponge having a potent anti-angiogenic activity, was executed. The syntheses and their biological evaluation of the oxime-modified analogues and bromine-modified analogues revealed that both the oxime moieties and bromine atoms in bastadin 6 (1) play an important role to show the potent and selective anti-proliferative activity against human umbilical vein endothelial cells (HUVECs).

Bastadins, cyclic tetramers of brominated-tyrosine derivatives, selectively inhibit the proliferation of endothelial cells.

Eight bastadins, tetramers of brominated-tyrosine derivatives, were isolated from the marine sponge Ianthella basta, and their anti-proliferative activities against endothelial cells were examined. A structure-activity relationship study of these compounds revealed that a macrocyclic structure was crucial, and a bastarane-type skeleton was important for the selective activity of these bastadins against endothelial cells. A conformational analysis of the bastadins was also carried out by molecular mechanics calculation.

Asymmetric desymmetrization based on an intramolecular haloetherification: a highly effective and recyclable chiral nonracemic auxiliary, 2-exo-methyl-3-endo-phenyl-5-norbornene-2-carboxaldehyde, for meso-1,3- and meso-1,4-diols.

A new chiral auxiliary, a 3-endo-phenyl norbornene aldehyde derivative, which is a crystalline, very stable, and easily handled, was developed for the desymmetrization of meso-1,3- and meso-1,4-diols. The key step of the method, an intramolecular bromoetherification, proceeded in a highly diastereoselective manner. A four-step sequence, 1) acetalization, 2) intramolecular bromoetherification followed by acid hydrolysis, 3) protection of the alcohol, and 4) retrobromoetherification, transformed the meso-diols into optically active derivatives. The 3-endo-phenyl norbornene aldehyde derivative was simultaneously reformed and could be used repeatedly. This is the first chemical example of a single auxiliary that is applicable for highly enantioselective desymmetrization of meso-1,3- and meso-1,4-diols; to the best of our knowledge, this is the best chemical method available for the desymmetrization of meso-1,4-diols.

Oxidative reaction of oxindole-3-acetic acids.

The oxindole-3-acetic acids, oxidative metabolites of indole-3-acetic acid, were isolated from a byproduct of a corn starch manufacturing plant, and were further converted to the 3-hydroxyl derivatives in the presence of metal ion. The mechanical study was followed by a chemical analysis including other byproducts, and suggested the presence of an intermediate that had a radical at the C-3 position of oxindole-3-acetic acids.