著者

沖 俊一 竹内 富雄

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.40, no.1, pp.2-19, 1982-01-01 (Released:2010-01-22)

参考文献数

48

被引用文献数

14 14

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Our efforts toward the drug development of new potent antitumor anthracycline antibiotic Aclacinomycin A have been extended to the studies on biogenesis, structure-activity relationships and microbial and chemical transformations to produce more active and less toxic compounds than adriamycin. Since 1973 we have produced about 100 compounds : aclacinomycins, 2-hydroxyaclacinomycins, 13-methylaclacinomycins, 4-Ο- methylaclacinomycins, 11- hydroxyaclacinomycins, 4''' -dehydrorhodomycin Y, 11 -hydroxycinerubin A, rhodirubins, roseorubicins, baumycins, 4 - hydroxybaumycinols, feudomycins, 1 -hydroxydaunorubicinol, trisarubicinol, 4''' aminoaclacinomycin derivatives, cinerulosyl-2 - deoxyfucosylrhodosaminyldaunomycinone derivatives by fermentation, by microbial glycosidation and by chemical modification. The biosynthetic pathways that transform the hypothetical decaketide precursors of anthracyclinones to the appropriate end products were elucidated on the basis of the chemical structures of anthracyclines newly produced by feeding presumptive biosynthetic intermediates to mutants blocked in the biosynthesis of parent metabolites. Outline of fermentation and purification, structures of anthracycline antibiotics produced by microorgnisms, biosynthesis of anthracyclinones, biological activity and its relationships to chemical structure were reviewed.

著者

西村 吉雄 齋藤 仁 好川 博 近藤 信一 竹内 富雄

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 30 (ISSN:24331856)

巻号頁・発行日

pp.508-515, 1988-09-26 (Released:2017-08-18)

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The semi-synthetic podophyllotoxin glycosides, VP-16-213 (1) and VM-26 (2) showing a marked clinical efficacy and the intriguing mechanisms of action have stimulated interest in the synthesis of new active analogues of the podophyllotoxin glycoside. The systematic chemical modification of podophyllotoxins was studied. 1) Aminoglycosidic lignan variants (6, 7, etc.) of 4'-O-demethy1-1-epipodophyllotoxin were synthesized by a stereoselective BF_3-catalyzed coupling of 5 with the corresponding aminosugar derivatives. N-Alkylaminoglycosyl analogues (8, etc.) of 1 were also derived from 6. 2) Syntheses of all possible diastereomers (1, 6, 8, and 15-23) of 1, 6 and 8 were achieved via optical resolution of (±)-podophyllotoxin by glycosidation with D- and L-sugars. 3) Glycosidic variants of 1-β-hydroxy-α-peltatin and 1-β-hydroxy-8-O-methyl-a-peltatin (24-26) were synthesized by glycosidation of 28 and 29 with the corresponding sugar derivatives. 4) The syntheses of carbocyclic lignan variants (34-37) of 4'-O-demethyl-1-epipodophyllotoxin were achieved by coupling of 5 with chiral aminocyclitols. 5) 1-O-(2-Aminoethyl) ethers of 4'-O-demethyl-1-epipodophyllotoxin (38-42, etc.) were synthesized by coupling of 5 with the corresponding 2-aminoethanol derivatives, and with ethylene glycol followed by reductive amination of its aldehyde. Among all derivatives synthesized, 6 and 8 were found to have superior antitumor activity to 1.

著者

青柳 高明 国元 節子 竹内 富雄 梅沢 浜夫

出版者

公益財団法人 日本感染症医薬品協会

雑誌

The Japanese Journal of Antibiotics (ISSN:03682781)

巻号頁・発行日

vol.26, no.2, pp.109-114, 1973-04-25 (Released:2013-05-17)

参考文献数

20

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消化性潰瘍の成因と進行には種々の因子が関与しているが, 潰瘍の発生および増大に胃液内酸性プロテアーゼが大きな役割を果していることは明らかである。胃液内酸性プロテアーゼを抑制することは, 消化性潰瘍の治療および発生機序を解明することができるとの考察のもとに, 著者らは酸性プロテアーゼ阻害物質の探索研究をおこない, 放線菌培養濾液からペプスタチンを発見した1, 2)。ペプスタチンは, ペプシン, レニンおよびカテプシンDを含む酸性プロテアーゼに対して特異的な強い阻害活性をもつが, セリン酵素, チオール酵素などの中性およびアルカリ性プロテアーゼに対しては, 阻害活性を示さない3~6)。ペプスタチンは, 臨床分野において, 消化性潰瘍に有効であると報告されている7~13)。本稿では, ペプスタチンの酸性プロテアーゼに対する抑制作用および臨床的に応用しうる胃液内の酸性プロテアーゼ活性の定量的測定法について報告する。

著者

斉藤 仁 好川 博 西村 吉雄 近藤 信一 竹内 富雄 梅澤 濱夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.34, no.9, pp.3741-3746, 1986-09-25 (Released:2008-03-31)

参考文献数

11

被引用文献数

17 25

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D-(and L-)2, 6-Dideoxy-2-aminoglycosidic variants of 4'-O-demethyl-1-epipodophyllotoxin were synthesized by glycosidation of 4'-O-benzyloxycarbonyl- or 4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (6 or 14) with the corresponding aminosugar derivatives. 1-O-(2-Amino-2-deoxy-4 : 6-O-ethylidene-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (18) reacted with aldehydes in the presence of sodium cyanoborohydride, or reacted with α, β-unsaturated esters, or with α, β-unsaturated nitriles to yield the corresponding N-alkyl analogs. A number of the 4'-O-demethyl-1-epipodopyllotoxin β-D-aminoglycoside derivatives gave significant survival time increases in mice with leukemia L-1210. In particular, 1-O-(2-dimethylamino-2-deoxy-4 : 6-O-ethylidene-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (19) showed superior activity to VP-16-213 (etoposide, 1).

著者

高木 泰 土屋 務 三宅 俊昭 竹内 富雄 梅澤 純夫

出版者

The Society of Synthetic Organic Chemistry, Japan

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.50, no.2, pp.131-142, 1992-02-01 (Released:2009-11-16)

参考文献数

41

被引用文献数

3 4

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Anthracycline antibiotics, represented by daunorubicin and doxorubicin, are important antitumor agents widely used in clinical treatment. Their use is, however, restricted by the cardiotoxic character and other undesirable side-effects. To overcome these drawbacks and expand the utility, many efforts have been made for the past two decades. Recently we have synthesized a compound with strong antitumor activity and weak toxicity, 7-O- (2, 6-dideoxy-2-fluoro-α-L-talopyranosyl) adriamycinone, in which the glycosidic bond is comparatively stable in acid-catalyzed hydrolysis by the presence of highly electronegative fluorine atom at C-2'. This article describes the recent studies on the synthesis of the 2'-fluoroanthracycline antibiotics and their 14, 3', and 4'-substituted derivatives together with structure-activity relationship. It was found that R-configuration at C-2' having the fluorine is requisite to exhibit strong antitumor activity; thus (2'S) -fluoro and 2', 2'-difluoro analogs were devoid of activity. Synthesis of 2'-methoxyl analogs is also described.

著者

斉藤 仁 好川 博 西村 吉雄 近藤 信一 竹内 富雄 梅澤 濱夫

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.34, no.9, pp.3733-3740, 1986-09-25 (Released:2008-03-31)

参考文献数

42

被引用文献数

8 14

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D-(and L-)Aminoglycosidic variants of 4'-O-demethyl-1-epipodophyllotoxin were synthesized by glycosidation of 4'-O-benzyloxycarbonyl- or 4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (8 or 22) with the corresponding aminosugar derivatives. Cyclic acetals of 1-O-(2-amino-2-deoxy- and 3-amino-3-deoxy-β-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxins (13 and 21) gave a significant survival time increase in mice with leukemia L-1210, and showed superior activity to VP-16-213 (etoposide, 5).

著者

神戸 敏江 土屋 香誉子 堀 誠 浴本 久雄 高橋 良和 竹内 富雄

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.17, no.4, pp.527-530, 1994-04-15 (Released:2008-04-10)

参考文献数

5

被引用文献数

1

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Several antitumor anthracyclines, including those in preclinical stages, were examined for their action in reversing tumorous phenotypes of H- or K-ras 3T3 cells (NIH3T3 cells transformed by human H- or K-ras oncogene) into normal phenotypes, such as flattened cell morphology, anchorage dependent cell growth, etc. (referred to as anti-ras activity). The study elucidated relationships between the chemical structure of anthracyclines and the anti-ras activity. The human tumor cell line T24, which has a mutated H-ras gene, responded to the anthracyclines, as did K- or H-ras 3T3 cells, in respect to the phenotypic alterations. Pirarubicin was more than 4 times as active as aclarubicin in inhibiting the growth of solid tumors of K-ras 3T3 cells in nude mice, possibly reflecting a difference in anti-ras activity between the two antibiotics.