This review summarizes our recent studies on the synthesis of nitrogencontaining heterocycles using cyclizations of N-alkenylcarbamoylmethyl radicals. These reactions are classified into several types of ring closures including relatively difficult 4-exo-trig and 5-endo-trig cyclizations which provide β- and γ-lactams, respectively. Sulfur-controlled exo-selective aryl radical cyclizations onto enamides and radical translocation/cyclization of aryl radicals generated from 2-alkenyl- or 2-alkynyl-N-(o-halobenzoyl) pyrrolidines are also described. The particular emphasis has been placed on the applications of these methods to the synthesis of natural products.
Efficacy and safety data of liposomal drugs in a laboratory environment are often not reproduced on an industrial production scale. This is largely due to the fact that the colloid-chemical properties of the liposomes manufactured on a small scale are not reproduced in large scale production. Though the size and the electric charge of liposomes are measured and are adequately specified in relation to the bio-distributions in most developments of liposomes (1), uniformity of lipid components, exposure of bio-chemically important functional groups on the outer surface of liposomes (2), fixed aqueous layer thickness (FALT), number of the lipid bilayers, etc., are dependent upon the scale of production. Nevertheless these properties are not always exactly specified. Uniformity, especially of the functional groups on the membrane surface can be assesssed chemically or bio-chemically with fractionated samples, and FALT can be easily determined through electro-chemical means (3). In this review, colloid chemical characterization of liposomes is introduced, FALT as an example, and its importance in a quality control of a liposomal product in an industrial scale production is shown. Methoxy-polyethyleneglycol-diacylglycerol (PEG-DAG) with varying PEG chain length and acyl chains were synthesized, FALT of liposomes coated with PEG-DAG determined and tissue distribution in tumor bearing mice. The higher incorporation ratio of PEG-DAG into liposomal membrane was observed with PEG-DAG with short acyl chains (myristoyl) and a small PEG molecular weight (1000). The easier to incorporate, the easier to be stripped in the serum. The disposition data in the rats well reflected the colloid chemical and in vitro data of the PEG liposomes. Galactosyl-carbonyl-propionyl-polyethyleneglycol-diacylglycerol (Gal-PEG-DAG) with oxyethylene number, n=10, 20 and 40 were synthesized. The exposure of the galactose residue beyong the fixed aqueous layer of liposomes coated with Gal-PEG-DAG was monitored by a lectin, Ricinus communis agglutinin (RCA) induced agglutination, the half life in the blood after i.v. injection into rats, organ distribution determined and intrahepatic distribution studied. Only the liposomes containing the Gal-PEG10-DAG aggregated with the lectin, indicating that only with this derivative the galactose group was adequately exposed. The Gal-PEG10-DAG liposomes were cleared from the plasma with a half life of 0.3h. The plasma elimination could be attributed entirely to increased uptake by the liver. The increased liver uptake was almost entirely attributed to increased uptake by the non-parenchymal cell. Incorporation of PEG-DSPE in to the Gal-PEG10-DAG liposomes caused 1) a three-fold increase in blood circulation time, 2) a small but significant decrease in hepatic uptake after 20h and 3) a significant shift in intrahepatic distribution in favor of the hepatocytes, comparable to that of the control liposomes. In conclusion, therapeutic efficacy and safety of liposomes can be controlled by their colloid chemical, more exactly, surface chemical properties. By setting up reasonable quality control specification of the properties in laboratory and examining the specifications satisfied in upscaling, the efficacy and safety are reproduced in a large scale product.
Antitumor activity of Hypsizigus marmoreus, an edible mashroom, was investigated by in vivo bioassay. The aqueous extract, hereinafter referred to as YH, was tested against syngeneic tumor, Lewis lung carcinoma. YH was found to give a significant increase in life span when assayed using a solid tumor, Lewis lung carcinoma, by intraperitoneal administration, but not as much by oral administration. It was also found that YH have an inhibitory activity of spontaneous tumor metastasis in mice bearing Lewis lung carcinoma by intraperitoneal administration. YH significantly decreased the number of metastasized nodules. It was suggested by Winn test that antitumor and antimetasatic activities shown by YH was effective in increasing activity on immunological by competent cells.
The crude drug, Chotoko (Uncariae Uncis cam Ramlus), the hooks of Uncaria spp. (Rubiaceae), has been claimed to possess sedative and antispasmodic actions, and is contained in a Chinese traditional preparation, Chotosan, as a main crude drug. Examinations were made on the anti-convulsion effects of Choto-san and Chotoko against some animal models of epilepsy conducted by the stimulation of drugs or electricity. Oral administration of the Choto-san extract to mice at the doses of 1.0g/kg and 3.0g/kg tended to inhibit the glutamate-induced convulsion in a dose-dependent manner, and the effect of the Chotoko extract at a 3.0g/kg dose was significant, while both the extracts showed no activity against the picrotoxine-induced, strychinine-induced, and electroshock convulsions. The Choto-san preparation without Chotoko was inactive, and the activity of the Chotoko extract was more potent than that of the every crude drug comprising Choto-san, suggesting that Chotoko plays the most important role in the Choto-san prescription and contains some active compounds. Bioassay-guided fractionation of the Chotoko extract led to the location of the active components in the less polar alkaloids-containing fraction, from which three indole alkaloids, geissoschizine methylether (1), hirsuteine (2) and hirsutine (3), and an oxyindole alkaloid, isocorynoxeine (4) were isolated and identified. Oral administration of 1 and 2 to mice at the doses of 50, 100, and 200 mg/kg inhibited the glutamate-induced convulsion in a dose-dependent manner. The effect of 3, the dihydro derivative of 2, was less potent than those of 1 and 2. Compound 4 showed no activity at a 100 mg/kg dose compared with control. The above results support the Chinese herbal description of the antispasmodic action of Chotoko, and show that 1 and 2 contained in Chotoko must be mainly contributed to the activity. It is also suggested that Choto-san may be clinically available for treatment of epilepsy.
Sulfonylureas are widely used as oral hypoglycemic drugs in the treatment of non insulin dependent diabetes mellitus (NIDDM). Since sulfonylureas are usually taken for a long period, the compliance of the patients is very important. Therefore, for the improvement of the compliance of the patients, the development of a transdermal dosage form of sulfonylureas was attempted in this study. Glibenclamide (GLI) or chlorpropamide (CHL) was chosen as a principal agent and ointments were prepared by mixing 5% of GLI or CHL with a FAPG ointment base. Penetration and shearing stresses of the ointments were determined as physical characteristics of the ointments. There was no obvious difference of characteristics between the GLI ointment, or the CHL ointment and the FAPG ointment base. In drug release tests, the CHL ointment showed better release of the drug than the GLI ointment. In both ointments, comparatively rapid release of drug was observed in the initial 1 h, and continuous slow release was observed thereafter. When the ointments were applied on the back of male Wistar rats and the plasma glucose level was measured, both CHL and GLI ointments gave lower blood glucose levels than the control (FAPG base). At the all measuring points, the GLI ointment brought about significantly lower blood glucose levels than the control (p<0.01). Thus, it was demonstrated that sulfonylureas were absorbed through the skin and lowered the blood glucose levels. The results suggest the possibility of transdermal administration of sulfonylureas for the treatment of NIDDM.
Anti-tyrosinase activity in the constituents of Arctostaphylos uva-ursi was examined and 1, 2, 3, 6-tetra-O-galloyl-β-D-glucose, 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose, methyl gallate, gallic acid, and hydroquinone were isolated as active compounds.