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Hongbo Huang - One of the best experts on this subject based on the ideXlab platform.
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Angucycline glycosides from mangrove derived streptomyces diastaticus subsp scsio gj056
Marine Drugs, 2018Co-Authors: Chun Gui, Yena Liu, Zhenbin Zhou, Shanwen Zhang, Hongbo HuangAbstract:Nine new Angucycline glycosides designated urdamycins N1⁻N9 (1⁻9), together with two known congener urdamycins A (10) and B (11), were obtained from a mangrove-derived Streptomycesdiastaticus subsp. SCSIO GJ056. The structures of new compounds were elucidated on the basis of extensive spectroscopic data analysis. The absolute configurations of 6⁻9 were assigned by electronic circular dichroism calculation method. Urdamycins N6 (6) and N9 (9) represent the first naturally occurring (5R, 6R)-Angucycline glycosides, which are diastereomers of urdamycins N7 (7) and N8 (8), respectively.
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grincamycins i k cytotoxic Angucycline glycosides derived from marine derived actinomycete streptomyces lusitanus scsio lr32
Planta Medica, 2017Co-Authors: Yongxiang Song, Zhenzhu Lai, Huiping Ling, Jie Yuan, Yiwen Tao, Hongbo HuangAbstract:Three new Angucycline glycosides, designated grincamycin I (1), J (2), and K (3), together with the known congener A-7884 (4), were isolated from marine-derived actinomycete Streptomyces lusitanus SCSIO LR32. The structures of the new compounds were elucidated by comprehensive spectral data analysis. Compounds 2 and 4 exhibited antitumor activity against human cancer cells MDA-MB-435, MDA-MB-231, NCI-H460, HCT-116 and HepG2, and human normal breast epithelial cell MCF10A with IC50 values ranging from 0.4 to 6.9 µM. In addition, A-7884 (4) demonstrated antimicrobial activity against Micrococcus luteus with an MIC value of 1.95 µg/mL.
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cytotoxic rearranged Angucycline glycosides from deep sea derived streptomyces lusitanus scsio lr32
The Journal of Antibiotics, 2017Co-Authors: Xiangcheng Zhu, Yanwen Duan, Yun Zhang, Zhaomeng Cui, Zhen Wang, Hongbo HuangAbstract:Two new rearranged linear Angucycline glycosides, designated grincamycins G and H (1 and 2), together with three known congers P-1894B (vineomycin A1, 3), saquayamycin B (4) and vineomycin B2 (5), were obtained from marine-derived actinomycete Streptomyces lusitanus SCSIO LR32. The structures of 1 and 2 were elucidated by MS, 1D and 2D NMR techniques. Compounds 2-5 showed significant inhibitory effect on Jurkat T-cell proliferation with IC50 values of 3.0, 0.011, 0.037 and 0.3 μM, respectively.
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cytotoxic Angucycline class glycosides from the deep sea actinomycete streptomyces lusitanus scsio lr32
Journal of Natural Products, 2012Co-Authors: Hongbo Huang, Changsheng Zhang, Tingting Yang, Yongxiang Song, Bo Wang, Yun Zhang, Caiguo Huang, Jianhua JuAbstract:Five new C-glycoside Angucyclines, named grincamycins B-F (1-5), and a known Angucycline antibiotic, grincamycin (6), were isolated from Streptomyces lusitanus SCSIO LR32, an actinomycete of deep sea origin. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses, including MS and ID and 2D NMR experiments. All compounds except grincamycin F (5) exhibited in vitro cytotoxicities against the human cancer cell lines HepG2, SW-1990, HeLa, NCI-H460, and MCF-7 and the mouse melanoma cell line B16, with IC50 values ranging from 1.1 to 31 mu M.
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Cytotoxic Angucycline Class Glycosides from the Deep Sea Actinomycete Streptomyces lusitanus SCSIO LR32
2012Co-Authors: Hongbo Huang, Tingting Yang, Yongxiang Song, Bo Wang, Yun Zhang, Xiangmei Ren, Jing Liu, Aijun Sun, Caiguo HuangAbstract:Five new C-glycoside Angucyclines, named grincamycins B–F (1–5), and a known Angucycline antibiotic, grincamycin (6), were isolated from Streptomyces lusitanus SCSIO LR32, an actinomycete of deep sea origin. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses, including MS and 1D and 2D NMR experiments. All compounds except grincamycin F (5) exhibited in vitro cytotoxicities against the human cancer cell lines HepG2, SW-1990, HeLa, NCI-H460, and MCF-7 and the mouse melanoma cell line B16, with IC50 values ranging from 1.1 to 31 μM
Mikko Metsaketela - One of the best experts on this subject based on the ideXlab platform.
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structural and functional analysis of Angucycline c 6 ketoreductase lanv involved in landomycin biosynthesis
Biochemistry, 2013Co-Authors: Pasi Paananen, Pekka Mantsala, Pauli Kallio, Jarmo Niemi, Pekka Patrikainen, Laila Niiranen, Mikko MetsaketelaAbstract:Angucyclines are biologically active natural products constructed around a common benz[a]anthraquinone carbon frame. One key branching point in the biosynthesis of Angucyclines is the ketoreduction at C-6, which results in the opposite stereochemistry of landomycins and urdamycins/gaudimycins. Here we present the 1.65 A resolution crystal structure of LanV from Streptomyces cyanogenus S136 that is responsible for the 6R stereochemistry of landomycins. The enzyme displays the common architectural fold of short-chain alcohol dehydrogenases/reductases and contains bound nicotinamide adenine dinucleotide phosphate. Determination of the structure of LanV in complex with 11-deoxylandomycinone at 2.0 A resolution indicated that substrate binding does not induce large conformational changes and that substrate recognition occurs mainly through hydrophobic interactions. Analysis of the electron density map of the ternary complex revealed that the catalytic reaction had most likely proceeded backward in the crystal,...
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flavoprotein hydroxylase pgae catalyzes two consecutive oxygen dependent tailoring reactions in Angucycline biosynthesis
Biochemistry, 2011Co-Authors: Pauli Kallio, Mikko Metsaketela, Pekka Mantsala, Pekka Patrikainen, Jukkapekka Suomela, Jarmo NiemiAbstract:A simplified model system composed of a NADPH-dependent flavoprotein hydroxylase PgaE and a short-chain alcohol dehydrogenase/reductase (SDR) CabV was used to dissect a multistep Angucycline modification redox cascade into several subreactions in vitro. We demonstrate that the two enzymes are sufficient for the conversion of Angucycline substrate 2,3-dehydro-UWM6 to gaudimycin C. The flavoenzyme PgaE is shown to be responsible for two consecutive NADPH- and O2-dependent reactions, consistent with the enzyme-catalyzed incorporation of oxygen atoms at C-12 and C-12b in gaudimycin C. The two reactions do not significantly overlap, and the second catalytic cycle is initiated only after the original substrate 2,3-dehydro-UWM6 is nearly depleted. This allowed us to isolate the product of the first reaction at limiting NADPH concentrations and allowed the study of the qualitative and kinetic properties of the separated reactions. Dissection of the reaction cascade also allowed us to establish that the SDR reduct...
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crystal structures of two aromatic hydroxylases involved in the early tailoring steps of Angucycline biosynthesis
Journal of Molecular Biology, 2007Co-Authors: Hanna Koskiniemi, Mikko Metsaketela, Pekka Mantsala, Doreen Dobritzsch, Pauli Kallio, Hanna Korhonen, Gunter Schneider, Jarmo NiemiAbstract:Angucyclines are aromatic polyketides produced in Streptomycetes via complex enzymatic biosynthetic pathways. PgaE and CabE from S. sp PGA64 and S. sp. H021 are two related homo-dimeric FAD and NADPH dependent aromatic hydroxylases involved in the early steps of the Angucycline core modification. Here we report the three-dimensional structures of these two enzymes determined by X-ray crystallography using multiple anomalous diffraction and molecular replacement, respectively, to resolutions of 1.8 A and 2.7 A. The enzyme subunits are built up of three domains, a FAD binding domain, a domain involved in substrate binding and a C-terminal thioredoxin-like domain of unknown function. The structure analysis identifies PgaE and CabE as members of the para-hydroxybenzoate hydroxylase (pHBH) fold family of aromatic hydroxylases. In contrast to phenol hydroxylase and 3-hydroxybenzoate hydroxylase that utilize the C-terminal domain for dimer formation, this domain is not part of the subunit-subunit interface in PgaE and CabE. Instead, dimer assembly occurs through interactions of their FAD binding domains. FAD is bound non-covalently in the "in"-conformation. The active sites in the two enzymes differ significantly from those of other aromatic hydroxylases. The volumes of the active site are significantly larger, as expected in view of the voluminous tetracyclic Angucycline substrates. The structures further suggest that substrate binding and catalysis may involve dynamic rearrangements of the middle domain relative to the other two domains. Site-directed mutagenesis studies of putative catalytic groups in the active site of PgaE argue against enzyme-catalyzed substrate deprotonation as a step in catalysis. This is in contrast to pHBH, where deprotonation/protonation of the substrate has been suggested as an essential part of the enzymatic mechanism.
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artificial reconstruction of two cryptic Angucycline antibiotic biosynthetic pathways
ChemBioChem, 2007Co-Authors: Kaisa Palmu, Mikko Metsaketela, Pekka Mantsala, Keishi Ishida, Christian HertweckAbstract:Genome-sequencing projects have revealed that Streptomyces bacteria have the genetic potential to produce considerably larger numbers of natural products than can be observed under standard laboratory conditions. Cryptic Angucycline-type aromatic polyketide gene clusters are particularly abundant. Sequencing of two such clusters from Streptomyces sp. PGA64 and H021 revealed the presence of several open reading frames that could be involved in processing the basic angucyclic carbon skeleton. The pga gene cluster contains one putative FAD-dependant monooxygenase (pgaE) and a putatively bifunctional monooxygenase/short chain alcohol reductase (pgaM), whereas the cab cluster contains two similar monooxygenases (cabE and cabM) and an independent reductase (cabV). In this study we have reconstructed the biosynthetic pathways for aglycone synthesis by cloning and sequentially expressing the Angucycline tailoring genes with genes required for the synthesis of the unmodified Angucycline metabolite-UWM6-in Streptomyces lividans TK24. The expression studies unequivocally showed that, after the production of UWM6, the pathways proceed through the action of the similar monooxygenases PgaE and CabE, followed by reactions catalysed by PgaM and CabMV. Analysis of the metabolites produced revealed that addition of pgaE and cabE genes directs both pathways to a known shunt product, rabelomycin, whereas expression of all genes from a given pathway results in the production of the novel Angucycline metabolites gaudimycin A and B. However, one of the end products is most probably further modified by endogenous S. lividans TK24 enzymes. These experiments demonstrate that genes that are either inactive or cryptic in their native host can be used as biosynthetic tools to generate new compounds.
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partial activation of a silent Angucycline type gene cluster from a rubromycin β producing streptomyces sp pga64
The Journal of Antibiotics, 2004Co-Authors: Mikko Metsaketela, Kristiina Ylihonko, Pekka MantsalaAbstract:In the course of DNA-fingerprinting our strain collection for antibiotic biosynthesis genes, two different type II polyketide synthase (PKS) gene clusters were observed from Streptomyces sp. PGA64. Phylogenetic analysis placed these together with known rubromycin and Angucycline biosynthetic gene clusters. The host strain itself has a very clean production profile of secondary metabolites, which composes mainly of rubromycin beta under typical fermentation conditions. Sequencing of a 16.5 kb fragment from the putative Angucycline cluster revealed eight genes that were homologous to typical type II PKS genes responsible for synthesizing aromatic polyketides. These genes were especially similar to genes from known Angucycline biosynthetic gene clusters and also synteny to these clusters was observed. In addition, three genes were recognized that are needed for priming the minimal PKS complex before polyketide synthesis can initiate, but which are not normally found to cluster with antibiotic biosynthesis genes. A putative repressor gene that was dissimilar to repressor genes found from well-characterized antibiotic biosynthesis gene clusters was also discovered. Gene disruption of the repressor resulted in partial activation of the cluster and production of two Angucycline metabolites, UWM6 and rabelomycin. The results confirm that the DNA-fingerprinting method we have developed can be used to correctly detect compounds that are not visible in chemical screens.
Jurgen Rohr - One of the best experts on this subject based on the ideXlab platform.
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enzymatic total synthesis of rabelomycin an Angucycline group antibiotic
Organic Letters, 2010Co-Authors: Madan K Kharel, Pallab Pahari, Hui Lian, Jurgen RohrAbstract:A one-pot enzymatic total synthesis of Angucycline antibiotic rabelomycin was accomplished, starting from acetyl-CoA and malonyl-CoA, using a mixture of polyketide synthase (PKS) enzymes of the gilvocarcin, ravidomycin, and jadomycin biosynthetic pathways. The in vitro results were compared to in vivo catalysis using analogous sets of enzymes.
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on the acceptor substrate of c glycosyltransferase urdgt2 three prejadomycin c glycosides from an engineered mutant of streptomyces globisporus 1912 deltalnde urdgt2
Angewandte Chemie, 2006Co-Authors: Irfan Baig, Andriy Luzhetskyy, Madan K Kharel, Anton Kobylyanskyy, Lili Zhu, Yuriy Rebets, Bohdan Ostash, Andreas Bechthold, Victor Fedorenko, Jurgen RohrAbstract:The landomycins 1–4 produced by Streptomyces cyanogenus S-136 and S. globisporus 1912 are Angucycline antibiotics with a strong activity against various cancer cell lines, in particular against prostate cancer cell lines.[1–6] The landomycins are closely related to the urdamycins (e.g., urdamycin A (5)).[7–9] Both possess a polyketide-derived angucyclinone core and sugar moieties consisting of d-olivose and l-rhodinose building blocks. Major structural differences were found in the assembly of the sugar moieties and in the oxygenation pattern of the polyketide core moiety.[1, 4, 5, 10–12]
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functional analyses of oxygenases in jadomycin biosynthesis and identification of jadh as a bifunctional oxygenase dehydrase
Journal of Biological Chemistry, 2005Co-Authors: Yihua Chen, Jurgen Rohr, Chenchen Wang, Lisa Greenwell, Uwe Rix, Dirk Hoffmeister, Leo C. Vining, Keqian YangAbstract:A novel Angucycline metabolite, 2,3-dehydro-UWM6, was identified in a jadH mutant of Streptomyces venezuelae ISP5230. Both UWM6 and 2,3-dehydro-UWM6 could be converted to jadomycin A or B by a ketosynthase alpha (jadA) mutant of S. venezuelae. These Angucycline intermediates were also converted to jadomycin A by transformant of the heterologous host Streptomyces lividans expressing the jadFGH oxygenases in vivo and by its cell-free extracts in vitro; thus the three gene products JadFGH are implicated in catalysis of the post-polyketide synthase biosynthetic reactions converting UWM6 to jadomycin aglycone. Genetic and biochemical analyses indicate that JadH possesses dehydrase activity, not previously associated with polyketide-modifying oxygenase. Since the formation of aromatic polyketides often requires multiple dehydration steps, bifunctionality of oxygenases modifying aromatic polyketides may be a general phenomenon.
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the oxidative ring cleavage in jadomycin biosynthesis a multistep oxygenation cascade in a biosynthetic black box
ChemBioChem, 2005Co-Authors: Uwe Rix, Keqian Yang, Yihua Chen, Chenchen Wang, Lisa Greenwell, Leo C. Vining, Fredilyn Lipata, Lily Remsing L Rix, Jurgen RohrAbstract:The antibiotic jadomycin B is derived from an Angucycline intermediate that undergoes oxidative ring cleavage and the unique incorporation of l-isoleucine into its polyketide backbone. To elucidate the enzymes and substrates involved in this key oxygenation event, we have investigated a region of the jad gene cluster that is located immediately downstream of the previously identified oxygenase genes jadF and jadG and contains a third putative oxygenase gene, jadH, as well as a potential hydrolase gene, jadK. Inactivation of jadG and jadH, respectively, led to the accumulation of several shunt products and a novel potential pathway intermediate, named prejadomycin. Production of these Angucyclines and the failure to generate a ring-cleavage product in various mutant strains illustrates the complex protein–protein interaction network within the oxygenase subcluster. Furthermore, these results demonstrate that both JadF and JadH display secondary dehydratase activities that contrary to their oxygenase activities, appear to be independent of the respective protein-complex binding partners. The polyketide glycoside antibiotic jadomycin B (2) and its aglycon jadomycin A (1) (Scheme 1) are produced by the soil bacterium Streptomyces venezuelae ISP5230 under stress conditions such as heat shock, phage infection, and particularly ethanol treatment. The jadomycin family possesses a unique nitrogen-containing pentacyclic benz[b]oxazolophenanthridine backbone that has been shown by precursor-directed biosynthesis with various amino acids as well as feeding experiments with C-labeled acetate to derive from the fusion of an l-amino acid, for exam-
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bioorganic chemistry deoxysugars polyketides and related classes synthesis biosynthesis enzymes
1997Co-Authors: Jurgen RohrAbstract:Chemical and biochemical aspects of deoxysugars and deoxysugar oligosaccharides.- The chemistry and biology of fatty acid, polyketide, and nonribosomal peptide biosynthesis.- Angucyclines: Total syntheses, new structures, and biosynthetic studies of an emerging new class of antibiotics.
Changsheng Zhang - One of the best experts on this subject based on the ideXlab platform.
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Discovery of Stealthin Derivatives and Implication of the Amidotransferase FlsN3 in the Biosynthesis of Nitrogen-Containing Fluostatins
MDPI AG, 2019Co-Authors: Chunshuai Huang, Yiguang Zhu, Chunfang Yang, Liping Zhang, Wenjun Zhang, Zhuangjie Fang, Changsheng ZhangAbstract:Diazobenzofluorene-containing atypical Angucyclines exhibit promising biological activities. Here we report the inactivation of an amidotransferase-encoding gene flsN3 in Micromonospora rosaria SCSIO N160, a producer of fluostatins. Bioinformatics analysis indicated that FlsN3 was involved in the diazo formation. Chemical investigation of the flsN3-inactivation mutant resulted in the isolation of a variety of Angucycline aromatic polyketides, including four racemic aminobenzo[b]fluorenes stealthins D–G (9–12) harboring a stealthin C-like core skeleton with an acetone or butanone-like side chain. Their structures were elucidated on the basis of nuclear magnetic resonance (NMR) spectroscopic data and X-ray diffraction analysis. A plausible mechanism for the formation of stealthins D–G (9–12) was proposed. These results suggested a functional role of FlsN3 in the formation/modification of N–N bond-containing fluostatins
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isolation structure elucidation and biosynthesis of benzo b fluorene nenestatin a from deep sea derived micromonospora echinospora scsio 04089
Tetrahedron, 2017Co-Authors: Xiaodong Jiang, Qingbo Zhang, Yiguang Zhu, Fangling Nie, Chunfang Yang, Liping Zhang, Xinpeng Tian, Changsheng ZhangAbstract:Abstract Benzofluorene-containing Angucyclines, such as lomaiviticins, kinamycins, and fluostatins, have attracted increasing attentions on chemical synthesis and biosynthesis due to their unique structures and potent biological activities. Our continuous searching for novel natural products from deep-sea derived actinomycetes led to the discovery of nenestatin A ( 1 ), a benzo[ b ]fluorene compound possessing a carbon scaffold similar to the monomeric lomaiviticins, from the deep sea-derived Micromonospora echinospora SCSIO 04089. In addition, the biosynthetic gene cluster of nenestatin A ( nes ) was identified by a genome sequencing approach and comparative bioinformatics analysis with the lomaiviticin biosynthetic gene clusters. The nes -gene cluster was further verified by in vivo gene disruption experiments to afford a biosynthetic intermediate homo-dehydrorabelomycin E ( 2 ). This study adds a new member to the growing family of benzofluorene Angucyclines and paves the way for further biosynthetic investigations.
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heterologous expression of fluostatin gene cluster leads to a bioactive heterodimer
Organic Letters, 2015Co-Authors: Chunfang Yang, Yiguang Zhu, Chunshuai Huang, Wenjun Zhang, Changsheng ZhangAbstract:The biosynthesis gene cluster (fls) for atypical Angucycline fluostatins was identified from the marine derived Micromonospora rosaria SCSIO N160 and was confirmed by gene knockouts and the biochemical characterization of a bifunctional oxygenase FlsO2. The absolute configuration of the key biosynthetic intermediate prejadomycin was determined for the first time by Cu Kα X-ray analysis. Heterologous expression of the intact fls-gene cluster in Streptomyces coelicolor YF11 in the presence of 3% sea salts led to the isolation of two new compounds: fluostatin L (1) and difluostatin A (2). Difluostatin A (2), an unusual heterodimer, exhibited antibacterial activities.
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Heterologous Expression of Fluostatin Gene Cluster Leads to a Bioactive Heterodimer
2015Co-Authors: Chunfang Yang, Yiguang Zhu, Chunshuai Huang, Wenjun Zhang, Changsheng ZhangAbstract:The biosynthesis gene cluster (fls) for atypical Angucycline fluostatins was identified from the marine derived Micromonospora rosaria SCSIO N160 and was confirmed by gene knockouts and the biochemical characterization of a bifunctional oxygenase FlsO2. The absolute configuration of the key biosynthetic intermediate prejadomycin was determined for the first time by Cu Kα X-ray analysis. Heterologous expression of the intact fls-gene cluster in Streptomyces coelicolor YF11 in the presence of 3% sea salts led to the isolation of two new compounds: fluostatin L (1) and difluostatin A (2). Difluostatin A (2), an unusual heterodimer, exhibited antibacterial activities
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cytotoxic Angucycline class glycosides from the deep sea actinomycete streptomyces lusitanus scsio lr32
Journal of Natural Products, 2012Co-Authors: Hongbo Huang, Changsheng Zhang, Tingting Yang, Yongxiang Song, Bo Wang, Yun Zhang, Caiguo Huang, Jianhua JuAbstract:Five new C-glycoside Angucyclines, named grincamycins B-F (1-5), and a known Angucycline antibiotic, grincamycin (6), were isolated from Streptomyces lusitanus SCSIO LR32, an actinomycete of deep sea origin. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses, including MS and ID and 2D NMR experiments. All compounds except grincamycin F (5) exhibited in vitro cytotoxicities against the human cancer cell lines HepG2, SW-1990, HeLa, NCI-H460, and MCF-7 and the mouse melanoma cell line B16, with IC50 values ranging from 1.1 to 31 mu M.
Zhenzhu Lai - One of the best experts on this subject based on the ideXlab platform.
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grincamycins i k cytotoxic Angucycline glycosides derived from marine derived actinomycete streptomyces lusitanus scsio lr32
Planta Medica, 2017Co-Authors: Yongxiang Song, Zhenzhu Lai, Huiping Ling, Jie Yuan, Yiwen Tao, Hongbo HuangAbstract:Three new Angucycline glycosides, designated grincamycin I (1), J (2), and K (3), together with the known congener A-7884 (4), were isolated from marine-derived actinomycete Streptomyces lusitanus SCSIO LR32. The structures of the new compounds were elucidated by comprehensive spectral data analysis. Compounds 2 and 4 exhibited antitumor activity against human cancer cells MDA-MB-435, MDA-MB-231, NCI-H460, HCT-116 and HepG2, and human normal breast epithelial cell MCF10A with IC50 values ranging from 0.4 to 6.9 µM. In addition, A-7884 (4) demonstrated antimicrobial activity against Micrococcus luteus with an MIC value of 1.95 µg/mL.