Novel selective inhibitors for human topoisomerase I, BM2419-1 and -2 derived from saintopin

Compounds BM2419-1 and -2 were isolated from a culture broth of a fungus Paecilomyces sp. BM2419. It was shown that these novel compounds were artifacts derived from saintopin, a dual inhibitor of topoisomerase I and II by independent processes. In the human topoisomerase I inhibition assay using the recombinant Saccharomyces cerevisiae, BM2419-1 and -2 inhibited selectively the yeast growth dependent on human topoisomerase I induction with IC50 values of 0.3 ng/ml and 6.0 ng/ml, respectively.     

Bisabosquals, novel squalene synthase inhibitors. I. Taxonomy, fermentation, isolation and biological activities

In the course of screening for yeast squalene synthase inhibitors, bisabosqual A was isolated from the culture broth of Stachybotrys sp. RF-7260. The related compounds bisabosquals B, C and D were also isolated from Stachybotrys ruwenzoriensis RF-6853. Bisabosquals inhibited squalene synthases. IC50 values of bisabosqual A against the microsomal squalene synthases from Saccharomyces cerevisiae, Candida albicans, HepG2 cell and rat liver were 0.43, 0.25, 0.95 and 2.5 microg/ml, respectively. Bisabosqual C exhibited inhibitory activities similar to bisabosqual A. Bisabosqual A showed broad spectrum antifungal activity in vitro.     

Novel human topoisomerase I inhibitors, topopyrones A, B, C and D. II. Structure elucidation

The structures of novel topoisomerase I inhibitors, topopyrones A, B, C and D were elucidated by spectral analysis of the chemical derivatives. These compounds are an anthraquinone type containing a fused 1,4-pyrone moiety. Topopyrones A and B contain a chlorine atom, however C and D do not. It was suggested that topopyrones B and D are converted from topopyrones A and C, respectively by Wessely-Moser type rearrangement.     

Arborcandins A, B, C, D, E and F, novel 1,3-beta-glucan synthase inhibitors: production and biological activity

Arborcandins A, B, C, D, E and F, which possess potent 1,3-beta-glucan synthase inhibitory activity, were isolated from the culture broth of a filamentous fungus, strain SANK 17397. Arborcandins are novel cyclic peptides, that are structurally different from known glucan synthase inhibitors such as echinocandins. The 1,3-beta-glucan synthases of Candida albicans and Aspergillus fumigatus were inhibited by arborcandins with IC50 ranging from 0.012 to 3 microg/ml. The apparent Ki value of arborcandin C for C. albicans and A. fumigatus were 0.12 microM and 0.016 microM, respectively. The inhibition against these two 1,3-beta-glucan synthases by arborcandin C was noncompetitive. These compounds exhibited potent fungicidal activity against Candida spp. with MIC ranging from 0.25 to 8 microg/ml. The growth of A. fumigatus was suppressed by arborcandins with concentrations ranging from 0.063 to 4 microg/ml.     

Kigamicins, novel antitumor antibiotics. I. Taxonomy, isolation, physico-chemical properties and biological activities

Novel antibiotics named kigamicin A, B, C, D, and E were discovered from the culture broth of Amycolatopsis sp. ML630-mF1 by their selective killing activity against PANC-1 cells only under a nutrient starved condition. Under a condition of nutrient starvation, kigamicins A, B, C, and D inhibited PANC-1 cell survival at 100 times lower concentration than in normal culture. Kigamicins showed antimicrobial activity against Gram-positive bacteria including methicillin resistant Staphylococcus aureus (MRSA). Kigamicin D inhibited the growth of various mouse tumor cell lines at IC50 of about 1 microg/ml.     

Guadinomines, Type III secretion system inhibitors, produced by Streptomyces sp. K01-0509. I: taxonomy, fermentation, isolation and biological properties

Enteropathogenic Escherichia coli (EPEC) expressing the Type III secretion system (TTSS) induced hemolysis of sheep blood cells. Using this assay, six structurally related compounds designated as guadinomines were isolated as inhibitors of TTSS-induced hemolysis by ion exchange column chromatography and HPLC from the culture broth of Streptomyces sp. K01-0509. Guadinomines A and B showed potent inhibition with IC50 values of 0.02 and 0.007 microg/ml, respectively, guadinomine D showed moderate activity (IC50: 8.5 microg/ml), while guadinomines C1 and C2 and guadinomic acid had no activity.     

Tyropeptins A and B, new proteasome inhibitors produced by Kitasatospora sp. MK993-dF2. I. Taxonomy, isolation, physico-chemical properties and biological activities

Tyropeptins A and B, new proteasome inhibitors, were isolated from the culture broth of Kitasatospora sp. MK993-dF2. They were purified using ethyl acetate extraction, silica gel column chromatography, Sephadex LH-20 column chromatography and HPLC. Tyropeptin A inhibited the chymotrypsin-like (ChT-L) and trypsin-like (T-L) activities of 20S proteasome with IC50 values of 0.1 microg/ml and 1.5 microg/ml respectively, but did not inhibit the peptidylglutamyl-peptide hydrolyzing (PGPH) activity of 20S proteasome at a concentration of 100 microg/ml. The inhibitory activities of tyropeptin A were about two times as strong as that of tyropeptin B. Taxonomy of the producing strain is also described.     

Kosinostatin,a quinocycline antibiotic with antitumor activity from Micromonospora sp. TP-A0468

Kosinostatin, a quinocycline antibiotic was isolated from the culture broth of an actinomycete strain TP-A0468 along with isoquinocycline B. The producing strain was isolated from the seawater sample collected in Toyama Bay and identified as Micromonospora sp. based on the taxonomic study. Kosinostatin was obtained from the culture fluid by solvent extraction and ODS column chromatography. Kosinostatin inhibited the growth of Gram-positive bacteria strongly (MIC=0.039 microg/ml) and Gram-negative bacteria and yeasts moderately (MIC= 1.56 approximately 12.5 microg/ml). It showed cytotoxicity against various cancer cell lines with the IC50 of 0.02 approximately 0.6 microm and inhibited human DNA topoisomerase Ila with the IC50 of 3 approximately 10 microM.     

Adxanthromycins A and B, new inhibitors of ICAM-1/LFA-1 mediated cell adhesion molecule from Streptomyces sp. NA-148. I. Taxonomy, production, isolation and biological activities

Two new inhibitors of ICAM-1/LFA-1 mediated cell adhesion molecule, adxanthromycins A and B were isolated from the cultured broth of a streptomycete strain. The strain was identified as Streptomyces sp. NA-148 from its morphological and physiological characteristics. Adxanthromycins A and B inhibited the formation of the JY cell aggregates from 1.5 microg/ml, respectively, in a dose dependent manner. Components A and B also inhibited a human T cell leukemia cell line SKW-3 adhesion to soluble ICAM-1 in a dose-dependent manner with an IC50 of 18.8 microg/ml and 25.0 microg/ml, respectively.     

SPF-32629 A and B, novel human chymase inhibitors produced by Penicillium sp

Two new human chymase inhibitors, SPF-32629A and B, were isolated from the cultured broth of Penicillium sp. SPF-32629. These structures were determined by spectroscopic methods and identified as new pyridone compounds. SPF-32629B was the carboxylated derivative of SPF-32629A. SPF-32629A and B specifically inhibited human chymase among four serine proteases tested with the IC50 of 0.25 and 0.42 microg/ml, respectively.     

Topostin, a novel inhibitor of mammalian DNA topoisomerase I from Flexibacter topostinus sp. nov. II. Purification and some properties of topostin

We describe the isolation of inhibitors of mammalian DNA topoisomerase I, named topostins, from a culture broth of Flexibacter topostinus sp. nov. and some properties of the inhibitors. Topostins A1, A2 and B were isolated by differential solubility in solvents, adsorption chromatography on silica gel and gel filtration on a Sephadex LH-20 column. Topostins A1, A2 and B had specific activities of 4,700, 16,000 and 22,000 U/mg, respectively. The most active metabolite topostin B comprised two components with MW of 567 and 553 in an equimolar ratio.     

Yatakemycin,a novel antifungal antibiotic produced by Streptomyces sp. TP-A0356

In the screening of novel antifungal compounds, yatakemycin was found in the culture broth of Streptomyces sp. TP-A0356. Yatakemycin was obtained by solvent extraction of the fermentation broth and chromatographic purification using ODS column and preparative HPLC. The structure of yatakemycin was elucidated by NMR and CID-MS/MS experiments as a novel antibiotic belonging to a family of CC-1065 and duocarmycins known to be DNA alkylating agents. Yatakemycin inhibited the growth of pathogenic fungi such as Aspergillus fumigatus and Candida albicans with the MIC values of 0.01-0.03 microg/ml, more potent than amphotericin B (MIC: 0.1-0.5 microg/ml) or itraconazole (MIC: 0.03-0.2 microg/ml). It also showed potent cytotoxicity against cancer cell lines with the IC50 of 0.01-0.3 microg/ml.     

Cyclo(dehydroala-L-Leu), an alpha-glucosidase inhibitor from Penicillium sp. F70614

A diketopiperazine (1) has been isolated from the culture broth of Penicillium sp. F70614 and its structure has been determined to be cyclo(dehydroala-L-Leu) by various spectroscopic analyses. This compound selectively inhibited yeast alpha-glucosidase and porcine intestinal alpha-glucosidase with IC50 values of 35 and 50 microg/ml, respectively. However, it did not show significant inhibitory effects against almond beta3-glucosidase, Aspergillus alpha-galactosidase, Escherichia coli beta-galactosidase and jack bean alpha-mannosidase.     

A-90289 A and B, new inhibitors of bacterial translocase I, produced by Streptomyces sp. SANK 60405

During the course of screening for translocase I inhibitors, the new liposidomycin-related compounds, A-90289 A and B, were isolated from a culture broth of Streptomyces sp. SANK 60405. The structural elucidations were carried out by NMR and high-resolution mass spectral analyses, and they were classified as members of the liponucleoside antibiotics group with a sulfate group at the C-2' position. A-90289 A and B inhibited bacterial translocase I with IC(50) values of 36.5?ng?ml(-1) and 33.8?ng?ml(-1), respectively.     

DNA topoisomerase I inhibitor, ergosterol peroxide from Penicillium oxalicum

Recently, we found that the MeOH extract of Penicillium oxalicum showed inhibitory activity towards DNA topoisomerase I. Subsequently, ergosterol peroxide, ergosterol, palmitoleic acid, and linoleic acid were isolated from the cultured mycelia of P. oxalicum. The structural determinations were based on physical and spectral analyses. Biological evaluation revealed that ergosterol peroxide inhibited the relaxation of supercoiled DNA (pBR322) induced by DNA topoisomerase I, and also showed marginal, selective cytotoxic activity against human colon tumor cells [COLO-205 (ED50=8.56 microg/mL].     

Interactions between cytochromes P450, glutathione S-transferases and Ghanaian medicinal plants

Inhibition of cytochrome P450s (CYPs) is a major cause of adverse drug-drug interactions. Alternatively, inhibition of glutathione S-transferases (GSTs) may increase harmful effects of electrophilic compounds or metabolites. In the present study, aqueous extracts of seven Ghanaian medicinal plants were investigated for their inhibitory potential towards recombinant human CYP1A2, CYP2C9, CYP2D6 and CYP3A4, heterologously expressed in Escherichia coli. Effects of these extracts on recombinant human GSTA1-1, GSTM1-1, GSTP1-1, human and rat cytosolic GSTs were also investigated. Seven extracts, including Phyllanthus amarus whole plant, leaf, stem and root, Cassia siamea and Momordica charantia, inhibited CYP1A2 and CYP2C9 with IC50 values ranging between 28.3-134.3microg/ml and between 63.4-425.9microg/ml, respectively. Similarly, both CYP2D6 and CYP3A4 were inhibited by five extracts including Phyllanthus amarus whole plant, leaf, stem and root and Cassia alata, with IC50 values ranging between 45.8-182.0microg/ml and between 79.2-158.8microg/ml respectively. Human and rat liver cytosolic GSTs were inhibited with IC50 values ranging between 25.2-95.5microg/ml and between 8.5-139.4microg/ml, respectively. GSTM1-1 was most susceptible to the inhibition by the extracts, with IC50 values ranging between 3.6-50.0microg/ml, whilst IC50 values of 8.9-159.0microg/ml and 68.6-157.0microg/ml were obtained for GSTA1-1 and GSTP1-1, respectively. These findings show a significant potential both for CYP- and GST-mediated herb-drug interactions of the Ghanaian medicinal plants investigated.     

Yaequinolones, new insecticidal antibiotics produced by Penicillium sp. FKI-2140. I. Taxonomy, fermentation, isolation and biological activity

New nine insecticidal antibiotics designated yaequinolones were isolated from the culture broth of the fungal strain Penicillium sp. FKI-2140 by solvent extraction, centrifugal partition chromatography and HPLC. Yaequinolones showed growth inhibitory activity against brine shrimp (Artemia salina). Among them, yaequinolone F has the most potent activity with MIC value of 0.19 microg/ml.     

TAN-1813, a novel Ras-farnesyltransferase inhibitor produced by Phoma sp. taxonomy, fermentation, isolation and biological activities in vitro and in vivo

A novel Ras-farnesyltransferase inhibitor designated TAN-1813 was isolated from the culture broth of a fungus strain, FL-41510, isolated as a plant endophyte. The producer was taxonomically characterized as Phoma sp. FL-41510. TAN-1813 inhibited rat brain farnesyltransferase and geranylgeranyltransferase I activity with IC50 values of 23 microg/ml and 47/microg/ml, respectively. TAN-1813 showed mixed-type inhibition with respect to farnesylpyrophosphate and noncompetitive inhibition with respect to a K-Ras C-terminal peptide. It also inhibited the in situ farnesylation of cellular Ras proteins in a K-ras transformant (NIH3T3/K-ras) of mouse embryonic fibroblast cell line NIH3T3. TAN- 1813 inhibited the proliferation of various human cancer cells, some of which harbor activated ras alleles, with IC50 values of 15 approximately 110 ng/ml as well as that of NIH3T3 and NIH3T3/K-ras cells with IC50S of 540 and 310 ng/ml, respectively. Flow cytometric analysis indicated that TAN-1813 arrests NIH3T3/K-ras cells at both G1 and G2/M phases of the cell cycle. In addition, TAN-1813 was found to induce morphological reversion of NIH3T3/K-ras cells from the transformed phenotype. Antitumor activity of TAN-1813 against human fibrosarcoma HT-1080 and NIH3T3/K-ras tumors in nude mice was also verified.     

FR901469, a novel antifungal antibiotic from an unidentified fungus No.11243. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological properties

FR901469 is a novel antifungal antibiotic produced by an unidentified fungus No.11243. This compound was isolated from the culture broth by solvent extraction, HP-20 and YMC ODS gel column chromatography, and lyophilization. FR901469 is a white powder which melts at 182 approximately 187 degrees C and possesses the molecular formula C71H116N14O23. This compound has good water solubility. FR901469 inhibited the activity of 1,3-beta-glucan synthase from Candida albicans with an IC50 value of 0.05 microg/ml, and displayed greater inhibitory activity than other 1,3-beta-glucan synthase inhibitors such as, WF11899A, echinocandin B, aculeacin A, and papulacandin B.     

Ferroverdins, inhibitors of cholesteryl ester transfer protein produced by Streptomyces sp. WK-5344. I. Production, isolation and biological properties

Streptomyces sp. WK-5344, a soil isolate, was found to produce structurally related inhibitors of cholesteryl ester transfer protein (CETP). New active compounds, designated ferroverdins B and C, were isolated along with known ferroverdin A from the fermentation broth by solvent extraction, ODS column chromatography and silica gel column chromatography. All ferroverdins showed a dose-dependent inhibitory activity against human CETP. The IC50 values were 21, 0.62 and 2.2 microM for ferroverdins A, B and C, respectively, indicating that ferroverdin B is one of the most potent CETP inhibitors of microbial origin.