Norio Kawahara

Suppressive effects of novel derivatives prepared from Aconitum alkaloids on tumor growth

SummaryLittle information has so far been reported regarding the antiproliferative properties of Aconitum alkaloids against human tumor cells despite of their intense toxicities. In the present study, the antitumor properties and radiation sensitizing effects were investigated by various types of novel derivatives prepared from Aconitum alkaloids. The antitumor properties were investigated against human tumor cell lines, A172, A549, HeLa and Raji, respectively, by a cell growth, a clonogenic assay, cell cycle distribution, cell cycle related molecules and γH2AX expression. The novel compounds derived from C20-diterupenoid alkaloids showed a significantly suppressive effect in all cell lines. In contrast, natural C19-norditerpenoid alkaloids and their derivatives showed either no effect or only a slight effect. One of the compounds also showed radiosensitizing properties on A549 cells. These effects are not related to either the cell cycle distribution, the enhancement of apoptosis or the γH2AX expression. Novel derivatives prepared from Aconitum alkaloids, not but natural alkaloids, clearly showed anti-proliferative activity in human tumor cell lines.

A simple preparation of (R)-(2-cyclopentenyl)acetic acid and (R)-(2-cyclohexenyl)acetic acid using β-diastereoselective radical cyclization in the presence of Lewis acid

Abstract The alkenyl radical generated from (−)-8-phenylmenthyl 7-iodo-2,6-heptadienoate smoothly cyclized to afford ( R )-(2-cyclopentenyl)acetate with 88% de in 90% yield. ( R )-(2-Cyclohexenyl)acetate was also obtained with 84% de in 72% yield under the same conditions. The presence of Lewis acid is essential for high diastereoselectivity and chemical yield.

Alkylation of 4-hydroxyproline ester derivatives. Diastereoselectivity guided by the anomeric effect and π-interaction

Abstract The alkylation of 4-hydroxyproline derivatives 7 and 1 2 with a range of alkylating reagents was examined. The stereoselectivity was found to be dependent on the reagent and the N-protecting group. This was explained by a concept based on the stereoelectronic effect and π-interaction.

Radical cyclization using a thioacetal group for radical generation

Abstract The generation and cyclization of several heterocyclic radicals were investigated. The hydrogen abstraction from 1,3-dithiane, 1,3-dithiolane, and 1,3-oxathiane rings by a benzophenone triplet generated the corresponding heterocyclic radicals, which gave the cyclized products by intramolecular addition to α,β-unsaturated esters. Diastereoselective radical cyclization using chiral acetals was also investigated.

Synthesis of (−)-TAN1251A using 4-hydroxy-l-proline as a chiral source

Abstract A new synthetic route of (−)-TAN1251A possessing an antimuscarinic activity was developed on the basis of alkylation of a trans-4-hydroxy- l -proline derivative and the subsequent construction of an azaspiro ring as key steps.

Induction of differentiation of human myeloid leukemia HL-60 cells by novel pyrimidine nucleoside analogs

New pyrimidine nucleoside analogs (18 compounds) were synthesized and their growth-inhibiting and differentiation-inducing activities on human myeloid leukemia HL-60 cells were examined. Some of the analogs were found to induce nitroblue tetrazolium (NBT) reducing activity in the HL-60 cells. The inducing activities of these compounds were compared at their concentrations for 50% inhibition of cell growth. TI-79 (3-benzyl-5-methyl-3-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine- 2,4(1H,3H)-dione) was a very effective inducer of NBT-reduction and of differentiation of the cells into mature granulocytes. The induction of NBT-reducing activity by TI-79 was inhibited by high concentrations of the natural nucleoside, adenosine. Other differentiation inducers, such as retinoic acid, 1 alpha,25-dihydroxyvitamin D-3 and staurosporin markedly enhanced the induction of differentiation of HL-60 cells by TI-79. Nucleoside analogs such as TI-79 should be useful for differentiation therapy of some types of myelogenous leukemia.

Total synthesis of (±)-TAN1251A

Abstract The first synthesis of novel type alkaloid (±)-TAN1251A possessing an antimuscarinic activity was achieved.

Synthesis of C-nor-D-homo-epiandrosterone: Studies on C-nor-D-homosteroids—IV☆

Abstract The synthesis of some C-nor-D-homopregnane and androstane derivatives from hecogenin is described. Hecogenin was degraded to III which in turn was converted to Va via IV. Manganese dioxide oxidation of Va yielded XVIIIa which was reduced to C-nor-D-homo-epiandrosterone (XXVa). This latter compound possesses the epiandrosterone configuration at each of the ring junctures.

7-endo Selective Friedel-Crafts type cyclization of vinyloxiranes linked to an ester group

Abstract Treatment of arylpropyl vinyloxiranes linked to ester with BF3 was found to produce seven-membered ring products in excellent yields. This reaction proceeded in an inversion fashion.

Determination and quantitative analysis of Aconitum alkaloids in plants by liquid chromatography—atmospheric pressure chemical ionization mass spectrometry

Abstract A high-performance liquid chromatography—atmospheric pressure chemical ionization mass spectrometry method was useful for the simultaneous determination of Aconitum alkaloids, kobusine, pseudokobusine, dehydrolucidusculine, lucidusculine, delcosine and 14-acetyldelcosine, found in the Aconitum yesoense var. macroyesoense. These compounds were chromatographed by definite elution in 10 min and were quantitated by selected-ion monitoring of the protonated molecules. The method is linear over the range 10 ng to 10 μg of alkaloids per injection. The detection limits of alkaloids were ca. 1–5 ng per injection.