The photochemistry of heterocyclic compounds is of importance in the field of pharmaceutical science because its research provides not only the useful methodology for the synthesis of novel heterocyclic compounds but also the crucial information for the photolability of drugs containing heterocycles. Furthermore, there has been a fundamental study on the photochemistry of heterocyclic compounds which contributes promisingly to biochemistry as well as photobiology. In the continuation of our studies for about two decades in above context, we observed some intriguing photochemical reactions which serve as novel synthetic methods for heterocyclic compounds and clarify the chemical feature in the photolability of drugs. The recent discovery of a novel class of heterocyclic N-oxide possessing the highly efficient photooxidation capacity is of particular interest and provides a functional mimic of iron oxenoid or oxygen being applicable as biomimetic tools to investigations on the enzymatic oxidation of biological and xenobiotic substances and on the oxidative damage of nucleic acids by active oxygen species. This review describes and discusses our own results obtained in the photochemical studies of heterocyclic compounds in the light of pharmaceutical science.
We have developed various effective methods for the synthesis of natural products. Two topics have been reviewed from our recent achievement. The first topic describes new synthetic methods based on the chemistry of allenylmethyltrimethylsilanes. The synthetic utility has been demonstrated in the syntheses of L-arcanose (19), L-olivomycose (21), a key synthetic precursor of antitumor anthracyclines 23, (-)-paeoniflorin (28), (+)-allokainic acid (56), and (-)-kainic acid (61). The second topic describes new methodology utilizing the Katsuki-Sharpless reaction. Based on titanium-tartrate mediated asymmetric epoxidation of prochiral σ-symmetrical divinylcarbinols, (+)-endobrevicomin (69), (-)-exobrevicomin (71), D-olivose (77), D-oleandrose (78), D-digitoxose (79), D-cymarose (80), (-)-citreoviridin (86), and (+)-verrucosidin (87) have been synthesized enantioselectively. A new practical method for the preparation of polyol chiral building blocks has been developed based on the Red-Al promoted intramolecular reductive cleavage of the epoxy alcohol 98 available from the divinylcarbinol 97. The synthetic utility of this method has been demonstrated by an expeditious synthesis of the compactin lactone 110. Lewis acid mediated cyclization using a chiral epoxy alcohol as an initiating functionality has also been developed. (+)-Brefeldin A (129) and a key C/D-ring synthon of vitamin D 135 have been prepared using this methodology.
Synthesis of a gene for an oncoprotein, ras p21 and its functions are described. Point mutations in hot spots of ras genes have been found in human cancer cells and produce activated p21 which result in transformation of cultured NIH3T3 cells. To produce normal and activated p21 in quantity for biochemical and structural studies, genes encoding these proteins were synthesized and expressed in E. coli. Normal and activated RAS proteins were tested for their GTPase activity and three dimensional structures were determined by X-ray crystallography. Transforming activities of the synthetic genes have been tested by transfecting their expression vectors to NIH3T3 cells and the synthetic activated genes were found to transform these cells indicating that the product of the activated gene is responsible for these malignant growth of the cells. These activities were proved to be inhibited by transfecting designed ribozyme genes. These synthetic genes were used to investigate mutagenesis of damaged bases such as 7, 8-dihydro-8-oxoguanine and thymine photodimers, by introducing the damaged base in hot spots of the oncogene. These unnatural bases in the ras gene were found to be mutagenic and cause malignant growth of NIH3T3 cells.
In addition to sympathetic vasoconstrictor nerves, nonadrenergic, non-cholinergic vasodilator nerves control the vascular tone. In cerebral arteries of various species of animals, nitric oxide (NO) is a potential candidate for the vasodilator transmitter. In rat mesenteric arterioles, calcitonin gene-related poptide (CGRP) functions as a transmitter. In guinea pig mesenteric arteries, multiple transmitters including NO and CGRP mediate the vasodilator response. The physiological and pathophysiological significance of vasodilator nerves is to be determined.
From the root of Scutellaria repens BUCH.-HAM ex D. DON, two new flavonoids (10, 11) and three new phenylethanoids (12-14) were isolated, together with nine known compounds. The structures of 10-14 were shown to be 5, 7, 2'-trihydroxy-6, 8-dimethoxyflavone, O-5-hydroxy-6, 8-dimethoxyflavone-7-yl β-D-glucuronopyranoside, O-2-(3-hydroxy-4-methoxyphenyl) ethyl O-2, 3-di-O-acethyl-α-L-rhamnopyranosyl-(1→3)-(4-O-trans-feruloyl)-β-D-glucopyranoside, O-2-(3-hydroxy-4-methoxyphenyl) ethyl O-α-L-rhamnopyranosyl-(1→3)-(4-O-cis-feruloyl)-β-D-glucopyranoside and O-2-(3-hydroxy-4-methoxyphenyl)-ethyl O-2, 3-di-O-acethyl-α-L-rhamnopyranosyl-(1→3)-(4-O-cis-feruloyl)-β-D-glucopyranoside, respectively, on the basis of the chemical and spectral data.
The amount of endotoxin in the serum was measured by the new assay method of endotoxin using a filtercup, Limulus amebocyte lysate, and immobilized histidine which is a specific adsorbent for endotoxin. The maximum recovery of endotoxin in the rabbit serum was obtained using acetate buffer (pH 5.5, μ=0.1) for the adsorption. Using this buffer, various kinds of endotoxin in water were adsorbed quantitatively on immobilized histidine, and the activity of the adsorbed endotoxin was well recovered. The value of the amount of endotoxin in the bovine serum measured by the new assay method, which includes heat treatment (70°C, 10 min) after separation followed by washing, was closer to that calculated from pyrogenic activities in rabbits than that measured by the PCA-Toxicolor method.
Ethyl 1-(difluoro-1, 3, 5-triazinyl)-2-methylindolizine-3-carboxylate was found to be a selective fluorescence derivatization reagent for primary and secondary amines. The reagent reacted with amines in aqueous acetonitrile in the presence of sodium hydroxide to give the corresponding fluorescent products, which could be separated on a TSK gel ODS-80TM reversed-phase column with aqueous methanol as eluent. 2-Phenethylamine and spermidine were used to investigate the derivatization conditions. The detection limits (signal-to-noise ratio=3) of each compound were 3 and 2 pmol per 10 μl injection volume, respectively. Alcohols, thiols and aromatic amines did not give any fluorescent products under these derivatization conditions.
A simple and precise method was established for the determination of honokiol (I) and magnolol (II) in kampo medicines containing Magnolia Barks using high-performance liquid chromatography with tetra-n-amylammonium bromide (TAA) as an ion-pair reagent. The optimum conditions for extracting both components from these kampo medicines were 15-min reflux with methanol. I and II were eluted within 9 min and 12 min, respectively, without interference from co-existing components using an ODS column and a mixture of water-acetonitrile containing 10 mM TAA as a mobile phase.