The Novel Gluconeogenesis Inhibitors FR225659 and Related Compounds that Originate from Helicomyces sp. No. 19353 I. Taxonomy, Fermentation, Isolation and Physico-chemical Properties

Ohtsu, Yoshihiro; Sasamura, Hiromi; Tsurumi, Yasuhisa; Yoshimura, Seiji; Takase, Shigehiro; Hashimoto, Michizane; Shibata, Toshihiro; Hino, Motohiro; Fujii, Takashi

doi:10.7164/antibiotics.56.682

Cited by 19 publications

(11 citation statements)

References 12 publications

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“…The peripheral blood glucose levels of db/db mice, an animal model of spontaneous type 2 diabetes, were significantly decreased in a dose‐dependent manner by the administration of 238 . Thus, this compound could be used as a novel lead to develop new hypoglycemic agents …”

Section: Bioactivities Of Quinoline and Quinazoline Alkaloidsmentioning

confidence: 99%

“…The peripheral blood glucose levels of db/db mice, an animal model of spontaneous type 2 diabetes, were significantly decreased in a dose-dependent manner by the administration of 238. Thus, this compound could be used as a novel lead to develop new hypoglycemic agents [325][326][327]. Activity-guided fractionation based on inhibition of diacylglycerol acyltransferase led to the isolation of evocarpine(141), dihydroevocarpine (142), 1-methyl-2-[(4Z,7Z)-4,7-decadienyl]-4(1H)-quinolone(163), and 1-methyl-2-[(6Z,9Z)-6,9-pentadecadienyl]-4(1H)-quinolone (164) from the fruits of E. rutaecarpa 328.…”

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confidence: 99%

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Biologically active quinoline and quinazoline alkaloids part I

Shang

Morris‐Natschke

Liu

et al. 2017

Medicinal Research Reviews

317

166

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Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

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Section: Bioactivities Of Quinoline and Quinazoline Alkaloidsmentioning

confidence: 99%

mentioning

confidence: 99%

Biologically active quinoline and quinazoline alkaloids part I

Shang

Morris‐Natschke

Liu

et al. 2017

Medicinal Research Reviews

317

166

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“…So we used the cell-assay system employing pyruvate as gluconeogenic precursor because we aimed to screen a wide range of compounds affect to a variety of targets. Therefore, although we had already 450 reported novel compounds with same screening system [8], we could obtain a novel compound, FR225654, which had completely different chemical and biological profiles from that. FR225654 has a highly oxygenated trans-decalin ring and a b-keto-enol in its main part, and has a characteristic side chain possessing a conjugated carboxylic acid and a tri-substituted olefin [9].…”

Section: Discussionmentioning

confidence: 99%

The Novel Gluconeogenesis Inhibitor FR225654 that Originates from Phoma sp. No. 00144

Ohtsu

Sasamura²,

Tanaka³

et al. 2005

J Antibiot

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FR225654, a novel gluconeogenesis inhibitor, was isolated from the culture broth of Phoma sp. No. 00144 and purified by adsorptive resin and reverse-phase column chromatography. This compound is a potent inhibitor of gluconeogenesis and is a promising candidate of anti-diabetic agent. Keywords gluconeogenesis, hepatocyte, diabetes, FR225654 IntroductionIt is estimated that there are about 7.4 million and 135 million patients of diabetes in Japan and in the world, respectively. The populations of diabetic patients are increasing accompanying with lack of exercise and excess of diet. In diabetes, the insulin resistance and/or deficiency causes a loss of glucose utilization in skeletal muscles and adipose tissues and an acceleration of glucose production in liver [1].Hepatic glucose production is brought by both of gluconeogenesis and glycogenolysis. The hyperproduction of glucose from liver in diabetes is based on a greater upregulation of the gluconeogenesis pathway compared with the glycogenolysis pathway [1]. Consequently, it is possible that inhibitors of gluconeogenesis are effective anti-diabetic drugs. To identify novel gluconeogenesis inhibitors, we used primary cultured rat hepatocytes to screen various microbial products for their ability to inhibit glucose production in vitro. During the course of this screening, we discovered a novel inhibitor named FR225654 (Fig. 1).FR225654 originated from the cultured broth of fungal strain No. 00144, which was isolated from a decayed leaf. This compound had potent inhibitory activity of gluconeogenesis in vitro and hypoglycemic activities in vivo. In this paper, we describe the taxonomy and the fermentation of fungal strain No. 00144 and the isolation

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“…IR bands (KBr) at 3480 (br)/1710 (vs) and 1730 (m) cm Ϫ1 were indicative of a carboxyl and an ester function, respectively. Since 1 was unstable in methanol-d 4 , and gave complicated signals due to two tautomeric forms in DMSO-d 6 , we screened deuterated solvents for a series of NMR measurement of 1, and found CD 3 CN to be suitable for this purpose. The 1 H NMR spectrum in CD 3 CN clearly showed 37 protons including an enol proton (d H 15.0), three olefinic ones and four singlet methyl groups.…”

Section: Was Observed At M/z 507 [Mϫh]mentioning

confidence: 99%

“…1), both of which show much weaker inhibition against gluconeogenesis than 1 does. With the same screening concept, we isolated FR225659 and its minor congeners before [6]. Interestingly, their structures and biological properties are quite different from those of 1.…”

Section: Was Observed At M/z 507 [Mϫh]mentioning

confidence: 99%

The Novel Gluconeogenesis Inhibitor FR225654 that Originates from Phoma sp. No. 00144

et al. 2005

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A novel gluconeogenesis inhibitor, FR225654 was isolated from the culture broth of Phoma sp. No. 00144. Spectroscopic analysis concluded that FR225654 has a highly oxygenated trans-decalin ring and b-keto-enol in its main part, and has a characteristic side chain possessing a conjugated carboxylic acid and tri-substituted olefin. Keywords gluconeogenesis, hepatocyte, diabetes, FR225654At present, 135 million people are suffering from diabetes in the world, and the number is still increasing. While the cause of diabetes still remains unclear, it is certain that high blood glucose levels damage various human tissues, leading to complications such as neuropathy, retinopathy and kidney diseases. Thus, control of blood glucose levels is a prerequisite for diabetes patients. By assuming that gluconeogenesis inhibitors might be useful for downregulation of blood glucose, we screened for those inhibitors from microbial metabolites and discovered FR225654 in a cultured broth of Phoma sp. No. 00144 [1,2]. Herein, the structure determination of FR225654 is discussed.In the negative ESI-MS spectrum, a deprotonated ion of FR225659 (1) was observed at m/z 507 [MϪH]Ϫ .Elemental analysis and number of carbon atoms deduced from 13 C NMR concluded its molecular formula to be C 27 H 40 O 9 (calcd. for C 27 H 40 O 9 · 1/2H 2 O C 62.65, H 7.98; found C 62.22, H 7.97). IR bands (KBr) at 3480 (br)/1710 (vs) and 1730 (m) cm Ϫ1 were indicative of a carboxyl and an ester function, respectively. Since 1 was unstable in methanol-d 4 , and gave complicated signals due to two tautomeric forms in DMSO-d 6 , we screened deuterated solvents for a series of NMR measurement of 1, and found CD 3 CN to be suitable for this purpose. The 1 H NMR spectrum in CD 3 CN clearly showed 37 protons including an enol proton (d H 15.0), three olefinic ones and four singlet methyl groups. In addition, extremely broadened three proton signals were observed in the area of 5.5ϳ3.5 ppm, and assigned as exchangeable. A pair of protons assigned to a disubstituted olefin resonates at 7.77 (d, Jϭ5 Hz) and 5.98 (d, Jϭ5 Hz) ppm, of a highly polarized olefin. The 13 C NMR and HSQC spectra in CD 3 CN showed six methyl, five methylene, eight methine and eight quaternary carbons. Signals for a saturated ketone (d C

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The Novel Gluconeogenesis Inhibitors FR225659 and Related Compounds that Originate from Helicomyces sp. No. 19353 I. Taxonomy, Fermentation, Isolation and Physico-chemical Properties

Cited by 19 publications

References 12 publications

Biologically active quinoline and quinazoline alkaloids part I

Biologically active quinoline and quinazoline alkaloids part I

The Novel Gluconeogenesis Inhibitor FR225654 that Originates from Phoma sp. No. 00144

The Novel Gluconeogenesis Inhibitor FR225654 that Originates from Phoma sp. No. 00144

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