Acquired immunodeficiency syndrome(AIDS) is a pandemic immunosuppressive disease which results in life-threatening opportunistic infections and malignancies. A retrovirus, designated human immunodeficiency virus (HIV), has been isolated and identified as the etiologic agent of this disease. Recently, some compounds have been evaluated for their inhibitory effects on HIV replication in vitro, e.g. ribavirin, phosphonoformic acid, recombinant interferon-α, 2, 3'-azido-2', 3'-dideoxythymidine, 2', 3'-dideoxynucleosides and glycyrrhizin. Clinical trials have been also initiated with most of these compounds, although results of these trials cannot be fully interpreted. In view of the uniqueness of HIV infection it is essential to understand the mode of infection and replication of HIV for the chemotherapeutic approaches to the treatment of AIDS.
Water-soluble cyclophanes constitute a promising group of totally artificial hosts having hydrophobic cavities to capture organic guests in water. A series of novel water-soluble cyclophanes, Cpnn (4, 14) and QCPnn (34), were designed and synthesized with two diphenylmethane skeletons as structural units for well-defined hydrophobic cavities. An X-ray crystallographic study on the host-guest complexes proved the formation of inclusion complexes of well-defined structure; this is the first direct evidence of inclusion complex formation by a water-soluble cyclophane. The formation of well-defined inclusion complexes in water was also confirmed by a detailed proton nuclear magnetic resonance study. The complex formation in water was found to occur with remarkable selectivity towards aromatic guests. This aromatic selectivity was reasonably attributed to the formation of well-defined hydrophobic cavities fitting well with the aromatic rings of the guests. The above findings on the molecular recognition function of CPnn and QCPnn led to rational design and syntheses of host molecules aiming at inclusion of bulky aliphatic guests (51, 52), as well as at chiral recognition (55, 56) and dual binding (60) of aromatic guests.
For the purpose of the synthesis of indole alkaloids having alkyl substituents at the benzene portion of the indole, two novel procedures are developed for synthesizing 4, 5, 6 and/or 7-alkylindole derivatives from pyrrole derivatives. One is a stannic chloride or ptoluenesulfonic acid catalyzed cyclization reaction of compounds 20 and 24, which are synthesized by a stannous chloride mediated reaction of 1-trimethylsily-1, 3-butadiene derivatives 23 on the endoperoxide of 1-methoxycarbonylpyrrole 13. Another is a sulfuric acid catalyzed ring cyclization of 1-tosylpyrrole derivatives 74 to afford 4, 6 and 7-alkyl substituted indoles. These results are applied to the synthesis of (±)-α-cyclopiazonic acid 5, a mycotoxin isolated first from Penicillium cyclopium, teleocidin A-1 8a and A-2 8b, tumor promoters, and N-alkylergolines and their D-nor or D-homo derivatives, 81, 82, and 83.
Inhibitory effects of caffeoylquinic acids isolated from leaves of Artemisia species and other related compounds on the lipoxygenase dependent peroxidation of linoleic acid were studied by kinetic and electron spin resonance(ESR) measurements. The order of inhibition activity was as follows : 3, 5-dicaffeoylquinic acid (ID50=2.0×10-5 M)=rosmarinic acid > geraniin (2.8×10-5 M)>α-tocopherol (3.7×10-5 M)>chlorogenic acid (7.5×10-5 M)=caffeic acid>ferulic acid (2.5×10-4 M). This order coincided well with that obtained from the measurement of radical scavenging activities of these compounds against 1, 1-diphenyl-2-picryl hydrazyl. The inhibition profile of these compounds on lipid peroxidation in the lipoxygenase system was quite similar to those obtained previously in the biological systems of rat liver mitochondria and microsomes. In the separate ESR measurements in alkaline dimethyl sulfoxide solution, all caffeoyl-quinic acids exhibited relatively stable ESR signals assigned as a radical derived from the one-electron oxidation of dihydroxyphenyl group. From these results, it was concluded that the radical scavenging mechanism is commonly operative in both chemical and biological peroxidation systems.
In order to explore the scope of an unusual displacement reaction to form 3-phenyl-10H-benzo[b]pyridazino[4, 5-e][1, 4] thiazine-4(3H)-one(IIa) in the reaction of 5-(o-amino-phenylthio-4-chloro-2-phenyl-3(2H)-pyridazinone(Ia) with sodium ethoxide, the behavior of 2-methyl or 2-hydropyridazinone derivatives(Ib or Ic) against sodium ethoxide or sodium hydroxide were examined. Among them Ib underwent an unusual displacement reaction to afford 3-methylthiazine derivative(IIb), 4-(o-aminophenylthio)-5-ethoxy-2-methyl-3(2H)-pyridazinone(XIb) or 4-(o-aminophenylthio)-5-hydroxy-2-methyl-3(2H)-pyridazinone(XII), but Ic did not undergo it.
A series of 3-alkylthio-5-aryl-1, 2, 4-triazines were synthesized by the condensation of arylglyoxal with S-alkylthiosemicarbazide hydrogen halide in the presence of triethylamine. 3-Substituted 5-aryl-1, 2, 4-triazines were prepared by the nucleophilic substitution of 5-aryl-3-methylsulfonyl-1, 2, 4-triazine with O, N, C-nucleophiles. These compounds were evaluated for antifungal activity against Pyricularia oryzae. The protective effects on rice blast, sheath blight, cucumber powdery mildew were also determined by pot tests. The structure-activity relationship are discussed.
When isolated pancreatic islets were exposed extracellularly for 5 min to oxygen radicals generating a system of hypoxanthine-xanthine oxidase (HX-X.O. system), glucose-induced insulin release from the islets was inhibited, indicating a high sensitivity of β-cell to the oxygen radicals. Addition of superoxide dismutase (SOD) together with catalase to the HX-X.O. system almost completely prevented the inhibition of the insulin release, suggesting that the islets were injured by some oxygen radicals produced by the reaction with O2- and H2O2. Iron-chelator, diethylentriaminepentaacetic acid (DETAPAC) and iron-binding protein, apotransferrin also protected the inhibition of the insulin release, suggesting the possible participation of a trace iron in the cell injury caused by 02 and H2O2. Mannitol, the scavenger of hydroxyl radicals, protected the cell from oxidative damage but methylthiourea and dimethylthiourea had little effect. These results suggest that some oxygen radicals generated an extracellularly attack to the pancreatic islets and result in the inhibition of glucose-induced insulin release.
Inclusion complexes of anticancer drug 1-hexylcarbamoyl-5-fluorouracil(HCFU) with β-cyclodextrin(β-CyD), heptakis(2, 6-di-O-methyl)-β-CyD(DM-β-CyD) and heptakis (2, 3, 6-tri-O-methyl)-β-CyD(TM-β-CyD) in the molar ratio of 1 : 1 were prepared, and their dissolution, release from a suppository base and oral or rectal absorption behaviors were examined. The apparent rates of dissolution and the release of the drug from Witepsol H-15 suppositories were significantly increased by the formation of inclusion complexes, particularly by DM-β-CyD. In addition, DM-β-CyD markedly inhibited the degradation of HCFU to give 5-fluorouracil in the small and rectal intestinal tracts. The plasma levels of HCFU after oral or rectal administration of the chemically stable and rapid dissolving form of DM-β-CyD complex to rabbits were significantly higher than those of the drug alone. The results indicate that the increase in oral or rectal bioavailability of HCFU by means of DM-β-CyD complexation may allow a reduction of the dose, which is a promising advantage for the decrease in side effects of anticancer agents.
The role of the chymotrypsin inhibitor, 4-(4-isopropylpiperazinocarbonyl)phenyl 1, 2, 3, 4-tetrahydro-1-naphthoate methanesulfonate (FK-448) in the promoting effect on the intestinal absorption of insulin was studied. After administration of insulin(63U/kg) into the intestinal loop of the rat, the immunoreactive insulin(IRI) level in the portal plasma reached 49±2μU/ml, but the blood glucose level remained unchanged. When insulin was administered at the same dose with FK-448(20mg/kg), the IRI level increased to 331±91 μU/ml and the blood glucose level was decreased by 40% as compared with that before administration. The percentage of insulin absorption was estimated to be about 0.7(7 times over control) by using the area under the plasma IRI concentration-time curve(AUC) after intramesenteric venous administration of known amounts of insulin. When insulin alone was administered into the intestinal loop after washing for 30 min with Krebs-Henseleit solution, the AUC was not significantly different from that without washing. This means that insulin administered into the intestine is degraded by digestive enzymes adsorbed onto the mucosal glycocalyx or those in the mucous membrane. To clarify the role of FK-448 in its promoting effect on the intestinal absorption of insulin, the influence on the permeability of intestinal mucosa was examined by measuring the extent of exsorption of sulfanilic acid into the small intestine. FK-448 exhibits no enhanced permeability of the intestinal mucosa which accounts for the observed promoting effect on the intestinal absorption of insulin. Therefore, the promoting effect of FK-448 on the intestinal absorption of insulin was considered to be based on the inhibition of proteolytic enzyme(s), but the results above mentioned could not reveal where insulin administered into the intestinal tract was mainly degraded.