Synthesis and in Vitro Cytotoxicity Evaluation of Jadomycins.

Jadomycins, which are benzo[b]phenanthridine-type alkaloids isolated from Streptomyces venezuelae ISP5230, exhibit cytotoxic activity against multidrug-resistant breast cancer cells. We have previously achieved the total synthesis of jadomycins using the direct arylation of juglone as a key step. In this study, we achieved the total synthesis of jadomycin T and jadomycin aglycons using L-threonine and 1-amino-2-propanol as nitrogen sources. Additionally, we evaluated the cytotoxic activity of eight compounds, including glycosides, jadomycin T, and their corresponding aglycons, in eight types of tumor cells. The evaluated jadomycins tended to exhibit stronger cytotoxic activity as aglycons than as glycosides. Although the presence of a 1,3-oxazolidine ring derived from an amino acid was not essential, the presence of the 1,3-oxazolidine ring showed strong activity when the ring had a carboxyl group. Furthermore, compared to the non-natural isomer at a different position on the phenolic hydroxyl group, the naturally occurring phenanthroviridin aglycon exhibited stronger cytotoxic activity. In addition, this study suggests that jadomycins may become lead compounds for the treatment of brain tumors; however, further studies on their ability to penetrate the blood-brain barrier are required.

Palladium-Catalyzed ß-Arylation of Cyclic α,ß-Unsaturated O-Methyl Oximes with Aryl Iodides.

We report a Pd-catalyzed ß-arylation of cyclic α,ß-unsaturated O-methyl oximes with aryl iodides. This reaction shows complete regioselectivity and excellent functional group tolerance. ß-Arylation of 2-cyclohexen-1-one O-methyl oxime (existing as 2 : 1 E/Z mixture) with certain aryl iodides such as 4-iodoanisole affords only ß-arylated (E)-O-methyl oximes.

Synthesis and Aldose Reductase Inhibitory Activity of Botryllazine A Derivatives.

Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).

Green fluorescent protein chromophore derivatives as a new class of aldose reductase inhibitors.

A number of (Z)-4-arylmethylene-1H-imidazol-5(4H)-ones, which are related to the fluorescent chromophore of the Aequorea green fluorescent protein (GFP), have been synthesized and evaluated their in vitro inhibitory activity against recombinant human aldose reductase for the first time. The GFP chromophore model 1a, with a p-hydroxy group on the 4-benzylidene and a carboxymethyl group on the N1 position, exhibited strong bioactivity with an IC50 value of 0.36 µM. This efficacy is higher than that of sorbinil, a known highly potent aldose reductase inhibitor. Compound 1h, the 2-naphtylmethylidene analogue of 1a, exhibited the best inhibitory effect among the tested copounds with an IC50 value of 0.10 µM. Structure-activity relationship studies combined with docking simulations revealed the interaction mode of the newly synthesized inhibitors toward the target protein as well as the structural features required to gain a high inhibitory activity. In conclusion, the GFP chromophore model compounds synthesized in this study have proved to be potential drugs for diabetic complications.

Disaggregation of lipopolysaccharide by albumin, hemoglobin or high-density lipoprotein, forming complexes that prime neutrophils for enhanced release of superoxide.

We studied the interaction of LPS with albumin, hemoglobin or high-density lipoprotein (HDL), and whether the interaction affected the activity of LPS on neutrophils. These proteins disaggregated LPS, depending upon temperature and LPS:protein ratio. Albumin-treated LPS was absorbed by immobilized anti-albumin antibody and was eluted with Triton X-100, indicating that LPS formed a hydrophobic complex with albumin. Rd mutant LPS was not disaggregated by the proteins, and did not form a complex with the proteins. But triethylamine-treated Rd mutant LPS formed complexes. When LPS was incubated with an equal concentration of albumin and with polymyxin B (PMXB), PMXB-LPS-protein three-way complexes were formed. After removal of PMXB, the complexes consisted of 11-15 LPS monomers bound to one albumin or hemoglobin molecule. LPS primed neutrophils for enhanced release of formyl peptide-stimulated superoxide, in a serum- and LPS-binding protein (LBP)-dependent manner. Although LPS plus LBP alone did not prime neutrophils, albumin-, hemoglobin- or HDL-treated LPS primed neutrophils when added with LBP. Triethylamine-treated Rd mutant LPS primed neutrophils only when incubated with one of the proteins and with LBP. Thus, in addition to LBP, disaggregation and complex formation of LPS with one of these proteins is required for LPS to prime neutrophils.

Multiple evaluations of the removal of pollutants in road runoff by soil infiltration.

Groundwater replenishment by infiltration of road runoff is expected to be a promising option for ensuring a sustainable urban water cycle. In this study, we performed a soil infiltration column test using artificial road runoff equivalent to approximately 11-12 years of rainfall to evaluate the removal of pollutants by using various chemical analyses and bioassay tests. These results indicated that soil infiltration treatment works effectively to remove most of the pollutants such as organic matter (chemical oxygen demand (CODMn) and dissolved organic carbon (DOC)), P species, polycyclic aromatic hydrocarbons (PAHs), numerous heavy metals and oestrogenic activities. Bioassay tests, including algal growth inhibition test, Microtox and mutagen formation potential (MFP) test, also revealed effective removal of toxicities by the soils. However, limited amounts of NO3, Mn, Ni, alkaline earth metals, perfluorooctane sulphonate (PFOS) and perfluorooctane sulphonamide (FOSA) were removed by the soils and they possibly reach the groundwater and cause contamination.