Malettinins B−D:  New Polyketide Metabolites from an Unidentified Fungal Colonist of <i>Hypoxylon </i>Stromata (NRRL 29110)

Angawi, Rihab F.; Swenson, Dale C.; Gloer, James B.; Wicklow, Donald T.

doi:10.1021/np049625r

Cited by 18 publications

(28 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The resulting products were purified, structurally characterized, and tested for cytotoxicity to gain further insights into the relationships between the primary and secondary structural features of the gichigamins and their biological properties. Nine major products were obtained (24)(25)(26)(27)(28)(29)(30)(31)(32) from the hydrolysis of 1 (SI Appendix, Fig. S3A) and ECD spectra were collected and analyzed for each compound (SI Appendix, Fig.…”

Section: Partial Hydrolysis Of Gichigamins Reveals Structural Requirementioning

confidence: 99%

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mass-spectrometry-based metabolomics and molecular phylogeny data were used to identify a metabolically prolific strain of Tolypocladium that was obtained from a deep-water Great Lakes sediment sample. An investigation of the isolate's secondary metabolome resulted in the purification of a 22-mer peptaibol, gichigamin A (1). This peptidic natural product exhibited an amino acid sequence including several β-alanines that occurred in a repeating ααβ motif, causing the compound to adopt a unique right-handed 3 11 helical structure. The unusual secondary structure of 1 was confirmed by spectroscopic approaches including solution NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. Artificial and cell-based membrane permeability assays provided evidence that the unusual combination of structural features in gichigamins conferred on them an ability to penetrate the outer membranes of mammalian cells. Compound 1 exhibited potent in vitro cytotoxicity (GI 50 0.55 ± 0.04 μM) and in vivo antitumor effects in a MIA PaCa-2 xenograft mouse model. While the primary mechanism of cytotoxicity for 1 was consistent with ion leakage, we found that it was also able to directly depolarize mitochondria. Semisynthetic modification of 1 provided several analogs, including a C-terminus-linked coumarin derivative (22) that exhibited appreciably increased potency (GI 50 5.4 ± 0.1 nM), but lacked ion leakage capabilities associated with a majority of naturally occurring peptaibols such as alamethicin. Compound 22 was found to enter intact cells and induced cell death in a process that was preceded by mitochondrial depolarization.peptaibol | fungi | natural products | gichigamin | mitochondria N atural product chemical research has evolved in many extraordinary ways over the last decade largely due to the integration of powerful and accessible analytical chemistry (1, 2) and molecular biology (3, 4) tools. Some of these techniques have been applied toward the creation of natural product big-data sets in which genomic, metagenomic, metabolomic, and proteomic approaches are combined to obtain new insights into nature's remarkable chemical bounty (4-8). The predictive capabilities of these methods have helped guide efforts in several fertile areas of natural products research including the DNA cross-linking enediynes (9), bioactive cyanobacterial metabolites (10, 11), cytotoxic pentangular polyphenols (12), and thiopeptide antibiotics (13).The integration of analytical and molecular approaches is an effective way to find new natural product analogs that exhibit enhanced biological activities and improved pharmacological attributes (e.g., greater potency, better solubility, enhanced therapeutic index, etc.), but it also has the potential to uncover compounds with activities that are markedly dissimilar to other members of the queried chemical class. Nature is well known for its chemical repurposing capabilities, which allow populations of organisms to evolve new biological functions from existing molecular sc...

show abstract

Section: Partial Hydrolysis Of Gichigamins Reveals Structural Requirementioning

confidence: 99%

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Risinger²,

Mitchell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…stromata (Angawi et al, 2003(Angawi et al, , 2005. It is the first time that their production is reported in a Cladosporium sp.…”

Section: Introductionmentioning

confidence: 94%

“…The compounds were isolated by preparative reversed-phase HPLC. Known compounds 1-3 were readily identified by comparison of their spectroscopic ( 1 H NMR, UV and MS) data with literature values (Angawi et al, 2003(Angawi et al, , 2005.…”

Section: Structure Elucidationmentioning

confidence: 99%

“…The molecular formula of 4 being the same as for 2 and 3 suggested the compounds to be isomeric. In addition, the oneand two-dimensional NMR spectra of 4 ( 1 H, 13 C, DEPT, COSY, HSQC, and HMBC; see Table 3 and Supplementary Information) revealed the presence of considerable structural similarities with 2 and 3 (Angawi et al, 2005). The 1 H and 13 C NMR data of 4 showed resonances for three methyl, two methylene and two aliphatic methine groups, one oxygenated methane, one ketalic carbon and one carbonyl group as well as signals for six aromatic carbons one of which appeared to be oxygenated.…”

Section: Structure Elucidationmentioning

confidence: 99%

See 1 more Smart Citation

Malettinin E, an antibacterial and antifungal tropolone produced by a marine Cladosporium strain

et al. 2014

View full text Add to dashboard Cite

The isolation and structure elucidation of malettinins A-C (1-3) along with the new malettinin E (4) are described. The compounds were produced by the fungus Cladosporium sp. strain KF501, which was isolated from the German Wadden Sea. The malettinins are built up of tropolone/dihydropyran ring structures linked to a furan ring. The structure elucidation of the isolated compounds was achieved by means of one-and two-dimensional NMR spectroscopy supported by mass and UV data. The relative configuration of 4 was determined on the basis of single-crystal X-ray diffraction analysis. 1-4 exhibited antibacterial and antifungal activities when profiled against Xanthomonas campestris and Trichophyton rubrum. The influence of the chemical structure of the furan ring and of configurational changes on biological activities was observed.

show abstract

“…Among the 16 genera reported, Hypoxylon with 14 species is largely distributed in various marine and terrestrial habitats, and producing a large variety of bioactive compounds among which cohaerins (Quang et al, 2005a;Surup et al, 2013), daldinins and daldinones (Quang et al, 2004;Gu et al, 2007), cytochalasin (Espada et al, 1997), fragiformin , mitorubrinols (Quang et al, 2005b), hypoxylonols (Fukai et al, 2012), hypoxylans (Kuhnert et al, 2015a), hypoxyvermelhotins , rickenyls (Kuhnert et al, 2015b), rutilins (Quang et al, 2005b), carneic acids , hymatoxins (Bodo et al, 1987;Borgschulte et al, 1991), malettinins (Angawi et al, 2005), hypoxysordarin (Daferner et al, 1999), lenormandins (Kuhnert et al, 2015c), nodulisporic acids (Bills et al, 2012), schweinitzin A (Linh et al, 2014), truncatones (Sudarman et al, 2016), macrocyclic polyesters 15G256 family (Schlingmann et al, 2002), and sporothriolide (Krohn et al, 1994;Surup et al, 2014;Cao et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Sporochartines A–E, A New Family of Natural Products from the Marine Fungus Hypoxylon monticulosum Isolated from a Sphaerocladina Sponge

et al. 2017

View full text Add to dashboard Cite

Four new sporochartines B-E were isolated from the marine fungus Hypoxylon monticulosum CLL-205, isolated from a sponge belonging to the Sphaerocladina order and collected in Tahiti coast. Sporochartine A (1), the first representative of this family was previously isolated from the same fungus. The structures of sporochartines B-E were elucidated using 1D and 2D NMR, HRMS and IR data. Their configurations were established according to ROE correlations and comparison with the absolute configuration of sporochartine A (1) previously obtained from X-ray analysis. Sporochartines A-D (2-4) may be derived from endo Diels-Alderase type catalysis and sporochartine E (5) from an exo Diels-Alderase catalysis. The spatial conformation of sporochartines drastically influences the results of the cytotoxic bioassay against HCT-116, PC-3, and MCF-7 human cancer cell lines.

show abstract

Malettinins B−D: New Polyketide Metabolites from an Unidentified Fungal Colonist of Hypoxylon Stromata (NRRL 29110)

Cited by 18 publications

References 17 publications

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

Malettinin E, an antibacterial and antifungal tropolone produced by a marine Cladosporium strain

Sporochartines A–E, A New Family of Natural Products from the Marine Fungus Hypoxylon monticulosum Isolated from a Sphaerocladina Sponge

Contact Info

Product

Resources

About