scholarly journals Molecular Networking Reveals Two Distinct Chemotypes in Pyrroloiminoquinone-Producing Tsitsikamma favus Sponges

Marine Drugs ◽  
2019 ◽  
Vol 17 (1) ◽  
pp. 60 ◽  
Author(s):  
Jarmo-Charles Kalinski ◽  
Samantha Waterworth ◽  
Xavier Siwe Noundou ◽  
Meesbah Jiwaji ◽  
Shirley Parker-Nance ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Biosynthetic Pathway ◽  
Dna Intercalation ◽  
Chemical Characteristics ◽  
Taxonomic Identification ◽  
Human Cell Lines ◽  
Molecular Networking ◽  
Drug Leads ◽  
Related Compounds ◽  
Chromatographic Isolation

The temperate marine sponge, Tsitsikamma favus, produces pyrroloiminoquinone alkaloids with potential as anticancer drug leads. We profiled the secondary metabolite reservoir of T. favus sponges using HR-ESI-LC-MS/MS-based molecular networking analysis followed by preparative purification efforts to map the diversity of new and known pyrroloiminoquinones and related compounds in extracts of seven specimens. Molecular taxonomic identification confirmed all sponges as T. favus and five specimens (chemotype I) were found to produce mainly discorhabdins and tsitsikammamines. Remarkably, however, two specimens (chemotype II) exhibited distinct morphological and chemical characteristics: the absence of discorhabdins, only trace levels of tsitsikammamines and, instead, an abundance of unbranched and halogenated makaluvamines. Targeted chromatographic isolation provided the new makaluvamine Q, the known makaluvamines A and I, tsitsikammamine B, 14-bromo-7,8-dehydro-3-dihydro-discorhabdin C, and the related pyrrolo-ortho-quinones makaluvamine O and makaluvone. Purified compounds displayed different activity profiles in assays for topoisomerase I inhibition, DNA intercalation and antimetabolic activity against human cell lines. This is the first report of makaluvamines from a Tsitsikamma sponge species, and the first description of distinct chemotypes within a species of the Latrunculiidae family. This study sheds new light on the putative pyrroloiminoquinone biosynthetic pathway of latrunculid sponges.

scholarly journals Targeted Isolation of Tsitsikammamines from the Antarctic Deep-Sea Sponge Latrunculia biformis by Molecular Networking and Anticancer Activity

Marine Drugs ◽  
2018 ◽  
Vol 16 (8) ◽  
pp. 268 ◽  
Author(s):  
Fengjie Li ◽  
Dorte Janussen ◽  
Christian Peifer ◽  
Ignacio Pérez-Victoria ◽  
Deniz Tasdemir
Keyword(s):  
Anticancer Activity ◽  
Deep Sea ◽  
Topoisomerase I ◽  
2D Nmr ◽  
Dna Intercalation ◽  
Molecular Networking ◽  
High Productivity ◽  
Chemical Structures ◽  
Dioxygenase Enzymes ◽  
The Antarctic

The Antarctic deep-sea sponge Latrunculia (Latrunculia) biformis Kirkpatrick, 1908 (Class Demospongiae Sollas, Order Poecilosclerida Topsent, Latrunculiidae Topsent) was selected for chemical analyses due to its potent anticancer activity. Metabolomic analysis of its crude extract by HRMS/MS-based molecular networking showed the presence of several clusters of pyrroloiminoquinone alkaloids, i.e., discorhabdin and epinardin-type brominated pyridopyrroloquinolines and tsitsikammamines, the non-brominated bis-pyrroloiminoquinones. Molecular networking approach combined with a bioactivity-guided isolation led to the targeted isolation of the known pyrroloiminoquinone tsitsikammamine A (1) and its new analog 16,17-dehydrotsitsikammamine A (2). The chemical structures of the compounds 1 and 2 were elucidated by spectroscopic analysis (one-dimensional (1D) and two-dimensional (2D) NMR, HR-ESIMS). Due to minute amounts, molecular modeling and docking was used to assess potential affinities to potential targets of the isolated compounds, including DNA intercalation, topoisomerase I-II, and indoleamine 2,3-dioxygenase enzymes. Tsitsikammamines represent a small class of pyrroloiminoquinone alkaloids that have only previously been reported from the South African sponge genus Tsitsikamma Samaai & Kelly and an Australian species of the sponge genus Zyzzya de Laubenfels. This is the first report of tsitsikammamines from the genus Latrunculia du Bocage and the successful application of molecular networking in the identification of comprehensive chemical inventory of L. biformis followed by targeted isolation of new molecules. This study highlights the high productivity of secondary metabolites of Latrunculia sponges and may shed new light on their biosynthetic origin and chemotaxonomy.

scholarly journals The Tripod for Bacterial Natural Product Discovery: Genome Mining, Silent Pathway Induction, and Mass Spectrometry-Based Molecular Networking

mSystems ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Daniela B. B. Trivella ◽  
Rafael de Felicio
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Natural Product ◽  
Biosynthetic Pathway ◽  
Genome Mining ◽  
Chemical Compounds ◽  
Gene Clusters ◽  
Tandem Mass ◽  
Molecular Networking ◽  
Natural Product Discovery

ABSTRACT Natural products are the richest source of chemical compounds for drug discovery. Particularly, bacterial secondary metabolites are in the spotlight due to advances in genome sequencing and mining, as well as for the potential of biosynthetic pathway manipulation to awake silent (cryptic) gene clusters under laboratory cultivation. Further progress in compound detection, such as the development of the tandem mass spectrometry (MS/MS) molecular networking approach, has contributed to the discovery of novel bacterial natural products. The latter can be applied directly to bacterial crude extracts for identifying and dereplicating known compounds, therefore assisting the prioritization of extracts containing novel natural products, for example. In our opinion, these three approaches—genome mining, silent pathway induction, and MS-based molecular networking—compose the tripod for modern bacterial natural product discovery and will be discussed in this perspective.

scholarly journals MS/MS-Based Molecular Networking Approach for the Detection of Aplysiatoxin-Related Compounds in Environmental Marine Cyanobacteria

Marine Drugs ◽  
2018 ◽  
Vol 16 (12) ◽  
pp. 505 ◽  
Author(s):  
Chi Ding ◽  
Li Pang ◽  
Zhao-Xun Liang ◽  
Kau Goh ◽  
Evgenia Glukhov ◽  
...  
Keyword(s):  
Public Health ◽  
Marine Cyanobacteria ◽  
Rrna Gene ◽  
Health Issues ◽  
Molecular Networking ◽  
Trichodesmium Erythraeum ◽  
Cyanobacterial Species ◽  
Its Rrna Gene ◽  
Organic Extracts ◽  
Related Compounds

Certain strains of cyanobacteria produce a wide array of cyanotoxins, such as microcystins, lyngbyatoxins and aplysiatoxins, that are associated with public health issues. In this pilot study, an approach combining LC-MS/MS and molecular networking was employed as a rapid analytical method to detect aplysiatoxins present in four environmental marine cyanobacterial samples collected from intertidal areas in Singapore. Based on 16S-ITS rRNA gene sequences, these filamentous cyanobacterial samples collected from Pulau Hantu were determined as Trichodesmium erythraeum, Oscillatoria sp. PAB-2 and Okeania sp. PNG05-4. Organic extracts were prepared and analyzed on LC-HRMS/MS and Global Natural Product Social Molecular Networking (GNPS) for the presence of aplysiatoxin-related molecules. From the molecular networking, six known compounds, debromoaplysiatoxin (1), anhydrodebromoaplysiatoxin (2), 3-methoxydebromoaplysiatoxin (3), aplysiatoxin (4), oscillatoxin A (5) and 31-noroscillatoxin B (6), as well as potential new analogues, were detected in these samples. In addition, differences and similarities in molecular networking clusters related to the aplysiatoxin molecular family were observed in extracts of Trichodesmium erythraeum collected from two different locations and from different cyanobacterial species found at Pulau Hantu, respectively.

scholarly journals Pathway for the Biosynthesis of the Pigment Chrysogine by Penicillium chrysogenum

2017 ◽  
Vol 84 (4) ◽  
Author(s):  
Annarita Viggiano ◽  
Oleksandr Salo ◽  
Hazrat Ali ◽  
Wiktor Szymanski ◽  
Peter P. Lankhorst ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Filamentous Fungi ◽  
Penicillium Chrysogenum ◽  
Biosynthetic Pathway ◽  
Biosynthetic Gene Cluster ◽  
Culture Broth ◽  
Yellow Pigment ◽  
Metabolic Potential ◽  
Content Type ◽  
Related Compounds

ABSTRACT Chrysogine is a yellow pigment produced by Penicillium chrysogenum and other filamentous fungi. Although the pigment was first isolated in 1973, its biosynthetic pathway has so far not been resolved. Here, we show that deletion of the highly expressed nonribosomal peptide synthetase (NRPS) gene Pc21g12630 ( chyA ) resulted in a decrease in the production of chrysogine and 13 related compounds in the culture broth of P. chrysogenum . Each of the genes of the chyA -containing gene cluster was individually deleted, and corresponding mutants were examined by metabolic profiling in order to elucidate their function. The data suggest that the NRPS ChyA mediates the condensation of anthranilic acid and alanine into the intermediate 2-(2-aminopropanamido)benzoic acid, which was verified by feeding experiments of a ΔchyA strain with the chemically synthesized product. The remainder of the pathway is highly branched, yielding at least 13 chrysogine-related compounds. IMPORTANCE Penicillium chrysogenum is used in industry for the production of β-lactams, but also produces several other secondary metabolites. The yellow pigment chrysogine is one of the most abundant metabolites in the culture broth, next to β-lactams. Here, we have characterized the biosynthetic gene cluster involved in chrysogine production and elucidated a complex and highly branched biosynthetic pathway, assigning each of the chrysogine cluster genes to biosynthetic steps and metabolic intermediates. The work further unlocks the metabolic potential of filamentous fungi and the complexity of secondary metabolite pathways.

scholarly journals Kite-Shaped Molecules Block SARS-CoV-2 Cell Entry at a Post-Attachment Step

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2306
Author(s):  
Shiu-Wan Chan ◽  
Talha Shafi ◽  
Robert C. Ford
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Cell Entry ◽  
Human Cell Lines ◽  
Structural Homology ◽  
Virus Attachment ◽  
Ic50 Values ◽  
Coronavirus Infection ◽  
Related Compounds ◽  
Infectious Cycle

Anti-viral small molecules are currently lacking for treating coronavirus infection. The long development timescales for such drugs are a major problem, but could be shortened by repurposing existing drugs. We therefore screened a small library of FDA-approved compounds for potential severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antivirals using a pseudovirus system that allows a sensitive read-out of infectivity. A group of structurally-related compounds, showing moderate inhibitory activity with IC50 values in the 2–5 μM range, were identified. Further studies demonstrated that these “kite-shaped” molecules were surprisingly specific for SARS-CoV-1 and SARS-CoV-2 and that they acted early in the entry steps of the viral infectious cycle, but did not affect virus attachment to the cells. Moreover, the compounds were able to prevent infection in both kidney- and lung-derived human cell lines. The structural homology of the hits allowed the production of a well-defined pharmacophore that was found to be highly accurate in predicting the anti-viral activity of the compounds in the screen. We discuss the prospects of repurposing these existing drugs for treating current and future coronavirus outbreaks.

A New Method for the Detection and Measurement of Polyaromatic Carcinogens and Related Compounds by DNA Intercalation

1996 ◽  
pp. 44-60 ◽  
Author(s):  
John J. Horvath ◽  
Manana Gueguetchkeri ◽  
Adarsh Gupta ◽  
Devi Penumatchu ◽  
Howard H. Weetall
Keyword(s):  
New Method ◽  
Dna Intercalation ◽  
Related Compounds

Combining Stable Isotope Labeling and Molecular Networking for Biosynthetic Pathway Characterization

2015 ◽  
Vol 87 (13) ◽  
pp. 6520-6526 ◽  
Author(s):  
Andreas Klitgaard ◽  
Jakob B. Nielsen ◽  
Rasmus J. N. Frandsen ◽  
Mikael R. Andersen ◽  
Kristian F. Nielsen
Keyword(s):  
Stable Isotope ◽  
Biosynthetic Pathway ◽  
Isotope Labeling ◽  
Stable Isotope Labeling ◽  
Molecular Networking

scholarly journals Bioconversion of Proposed Precursors into Theobroxide and Related Compounds

2011 ◽  
Vol 6 (12) ◽  
pp. 1934578X1100601
Author(s):  
Peng Li ◽  
Kosaku Takahashi ◽  
Ahmed Elkhateeb ◽  
Hideyuki Matsuura ◽  
Teruhiko Yoshihara ◽  
...  
Keyword(s):  
Related Compound ◽  
Biosynthetic Pathway ◽  
H Nmr ◽  
Related Compounds

We have previously reported a tetraketide origin for theobroxide and its related compound. In the present study, bioconversion of natural and deuterium-labeled precursors of this proposed biosynthetic pathway by Lasiodipoldia theobromae was investigated. Theobroxide was quantified after bioconversion from each proposed precursor. The transformation of the isotopically labeled precursor to products was tracked by 2H NMR measurement.

Topoisomerase I gene expression and cell sensitivity to camptothecin in human cell lines of different tumor types

1994 ◽  
Vol 5 (6) ◽  
pp. 645-649 ◽  
Author(s):  
Paola Perego ◽  
Giovannl Capranlco ◽  
Rosanna Supino ◽  
Franco Zunino
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Human Cell ◽  
Topoisomerase I ◽  
Human Cell Lines ◽  
Cell Sensitivity ◽  
Tumor Types ◽  
I Gene
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