Merocyclophanes C and D (1 and 2) were isolated from the cell extract of the cultured cyanobacterium UIC 10110. The structures were determined by one-dimensional nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry and confirmed by 2D NMR techniques. The absolute configurations were determined using electronic circular dichroism spectroscopy. Merocyclophanes C and D represent the first known analogues of the merocyclophane core structure, a recently discovered scaffold of [7,7] paracyclophanes characterized by an α-branched methyl at C-1/C-14; 1 and 2 showed antiproliferative activity against the MDA-MB-435 cell line with IC50 values of 1.6 and 0.9 μM, respectively. Partial 16S analysis determined UIC 10110 to be a Nostoc sp., and it was found to clade with UIC 10062 Nostoc sp., the only other strain known to produce merocyclophanes. The genome of UIC 10110 was sequenced, and a biosynthetic gene cluster was identified that is proposed to encode type I and type III polyketide synthases that are potentially responsible for production of the merocyclophanes; however, further experiments will be required to verify the true function of the gene cluster. The gene cluster provides a genetic basis for the observed structural differences of the [7,7] paracyclophane core structures.

Two new cyclic lipopeptides, trichormamides A (1) and B (2), were isolated from the cultured freshwater cyanobacterium Trichormus sp. UIC 10339. The strain was obtained from a sample collected in Raven Lake in Northern Wisconsin. The planar structures of trichormamides A (1) and B (2) were determined using a combination of spectroscopic analyses including HRESIMS and 1D and 2D NMR experiments. The absolute configurations of the amino acid residues were assigned by the advanced Marfey’s method after acid hydrolysis. Trichormamide A (1) is a cyclic undecapeptide containing two d-amino acid residues (d-Tyr and d-Leu) and one β-amino acid residue (β-aminodecanoic acid). Trichormamide B (2) is a cyclic dodecapeptide characterized by the presence of four nonstandard α-amino acid residues (homoserine, N-methylisoleucine, and two 3-hydroxyleucines) and one β-amino acid residue (β-aminodecanoic acid). Trichormamide B (2) was cytotoxic against MDA-MB-435 and HT-29 cancer cell lines with IC50 values of 0.8 and 1.5 μM, respectively.

•Two new carbamidocyclophanes were isolated from a cultured freshwater cyanobacterium Nostoc sp. (UIC 10274).•Carbamidocyclophane F showed potent anti-Mycobacterium tuberculosis activity in MABA and LORA assays.•Both carbamidocyclophane F and G exhibited antiproliferative activity against human melanoma and colon cancer cell lines.Two new (1 and 2) and three known (3–5) carbamidocyclophanes were isolated from a cultured freshwater cyanobacterium Nostoc sp. (UIC 10274) obtained from a sample collected at Des Plaines, Illinois. Their planar structures and stereoconfigurations were determined by extensive spectroscopic analysis including 1D/2D NMR experiments, HRESIMS as well as CD spectroscopy. Carbamidocyclophane F (1) showed potent anti-Mycobacterium tuberculosis activity in the microplate Alamar blue assay and low-oxygen-recovery assay with MIC values of 0.8 and 5.4 μM, respectively. Carbamidocyclophane F (1) also displayed antimicrobial activities against the gram positive bacteria Staphylococcus aureus and Enterococcus faecalis with MIC values of 0.1 and 0.2 μM, respectively. Carbamidocyclophane F (1) and Carbamidocyclophane G (2) both showed antiproliferative activity against MDA-MB-435 and HT-29 human cancer cell lines with IC50 values in the range from 0.5 to 0.7 μM.

Stigonemapeptin (1), a depsipeptide containing an Ahp (3-amino-6-hydroxy-2-piperidone) residue, was isolated from a bloom sample of the freshwater cyanobacterium Stigonema sp. collected from North Nokomis Lake in the Highland Lake District of northern Wisconsin. The planar structure was determined by 1D and 2D NMR experiments as well as HRESIMS analysis. The absolute configurations of the amino acids were determined using the advanced Marfey’s method after acid hydrolysis. Stigonemapeptin (1), characterized by the presence of the Ahp residue, also contained the modified amino acids Abu (2-amino-2-butenoic acid) and N-formylated Pro. Stigonemapeptin (1) showed in vitro elastase and chymotrypsin inhibitory activity, with IC50 values of 0.26 and 2.93 μM, respectively.

Chemical investigation of two cultured cyanobacteria, Westiellopsis sp. (SAG strain number 20.93) and Fischerella muscicola (UTEX strain number LB1829) led to the isolation of three hapalindole-type alkaloids, namely hapalindole X (1), deschloro hapalindole I (2), and 13-hydroxy dechlorofontonamide (3), along with ten known indole alkaloids (hapalindoles A, C, G, H, I, J, and U, hapalonamide H, anhydrohapaloxindole A, and fischerindole L) and fischerellins A and B. The structures were determined by a combination of spectroscopic analyses mainly based on 1D and 2D NMR and HRESIMS data. Selected compounds were evaluated for cytotoxicity and exhibited weak to moderate cytotoxicity against HT-29, MCF-7, NCI-H460, SF268, and IMR90 cells. All compounds, except hapalindole C, were evaluated for 20S proteasome inhibition and displayed either weak or no inhibition at 25 μg/mL. Selected compounds were also evaluated for antimicrobial activity, and hapalindoles X (1) and A, and hapalonamide H showed potent activity against both Mycobacterium tuberculosis and Candida albicans with MIC values ranging from 0.6 to 2.5 μM.

The extract of UIC 10035, a strain obtained from a sample collected near the town of Homestead, South Florida, showed antiproliferative activity against MDA-MB-435 cells. Bioassay-guided fractionation led to the isolation of a series of cyclic lipodecapeptides, named minutissamides E–L (1–8). The planar structures were determined by analysis of HRESIMS, tandem MS, and 1D and 2D NMR data, and the stereoconfigurations were assigned by LC–MS analysis of the Marfey’s derivatives after acid hydrolysis. Minutissamides E–L (1–8) exhibited antiproliferative activity against MDA-MB-435 cells with IC50 values ranging between 1 and 10 μM. The structures of minutissamides E–L (1–8) were closely related with those of the previously reported lipopeptides, puwainaphycins A–E and minutissamides A–D, characterized by the presence of a lipophilic β-amino acid and three non-standard amino acids NMeAsn, OMeThr and Dhb (α,β-dehydro-α-aminobutyric acid). The strain UIC 10035 was designated as cf. Anabaena sp. on the basis of morphological and 16S rRNA gene sequence analyses.

Sanctolide A (1), a 14-membered polyketide–nonribosomal peptide (PK–NRP) hybrid macrolide, was isolated from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79). The planar structure was determined using various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analyses. The relative configuration was assigned by J-based configurational analysis in combination with NOE correlations. The absolute configuration was determined by Mosher ester and enantioselective HPLC analyses. The structure of sanctolide A (1) features a rare N-methyl enamide and a 2-hydroxyisovaleric acid, which are incorporated to form a 14-membered macrolide ring structure, comprising a new type of cyanobacterial macrolides derived from a PKS–NRPS hybrid biosynthetic pathway.

The cell extract of a cultured terrestrial Nostoc sp. (UIC 10062), obtained from a sample collected at Grand Mere State Park in Michigan, displayed antiproliferative activity against the HT-29 human colon cancer cell line. Bioactivity-guided fractionation of the cell extract, combined with LC–MS analysis, led to the isolation of two cyclophanes, named merocyclophanes A and B (1 and 2). Their structures were determined by various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analyses. The stereoconfiguration was assigned on the basis of X-ray crystallographic and CD analyses. The structures of merocyclophanes A and B (1 and 2) established a hitherto unknown [7.7]paracyclophane skeleton in nature, as characterized by α-branched methyls at C-1/14. Merocyclophanes A and B (1 and 2) displayed antiproliferative activity against the HT-29 human colon cancer cell line with IC50 values of 3.3 and 1.7 μM, respectively.Graphical abstractInvestigation of Nostoc sp. (UIC 10062) led to the isolation of paracyclophanes, merocyclophanes A and B, with activity in the HT-29 cancer cell line (IC50 3.3 and 1.7 μM, respectively).Highlights► Two [7.7]paracyclophanes named merocyclophanes A and B were obtained. ► Both displayed antiproliferative activity against the HT-29 cancer cell line. ► Nostoc sp. (UIC 10062) was obtained from Grand Mere State Park in Michigan. ► Nostoc sp. was classified based on microscopic and 16S rRNA gene sequence analysis.

Two anabaenopeptin-type peptides, lyngbyaureidamides A and B, together with two previously reported peptides lyngbyazothrins C and D, were isolated from the cultured freshwater cyanobacterium Lyngbya sp. (SAG 36.91). Their structures were determined by spectroscopic and chemical methods. Lyngbyazothrins C and D were also able to inhibit the 20S proteasome with IC50 values of 7.1 μM and 19.2 μM, respectively, while lyngbyaureidamides A and B were not active at 50 μM.Graphical abstractTwo anabaenopeptin-type peptides, lyngbyaureidamides A (1) and B (2) together with two previously reported peptides lyngbyazothrins C and D were obtained from the cultured freshwater cyanobacterium Lyngbya sp. (SAG 36.91). Lyngbyazothrins C and D were found to inhibit the 20S proteasome with IC50 values of 7.1 μM and 19.2 μM, respectively.Highlights► Anabaenopeptin-type peptides named lyngbyaureidamides A and B are reported. ► The exocylic amino acids in lyngbyaureidamides have the D-configuration. ► Separating the two previously reported peptides, lyngbyazothrins C and D, was achieved. ► Lyngbyazothrins C and D inhibit the 20S proteasome.

A software package, termed “CYANOS”, has been developed to facilitate the data management and mining for natural product drug discovery efforts. This system allows for the management of data associated with field collections, culture conditions, harvests, extractions, chemical separations, and biological evaluation. This software utilizes a MySQL database for data storage, which allows for reporting and data mining via third party tools. In addition, a Web-based interface was constructed to allow for multiuser access from a variety of desktop platforms. The code for this system is freely available and has been released under the Illinois Open Source license.

Four cyclic decapeptides, minutissamides A–D (1–4), were isolated from the cultured cyanobacterium Anabaena minutissima (UTEX 1613). The planar structures were determined using various spectroscopic techniques including HRESIMS and 1D and 2D NMR experiments. The absolute configurations of the α-amino acid residues were assigned using Marfey’s method after acid hydrolysis. The absolute configuration of a β-amino acid residue was assigned by a combination of the advanced Marfey’s method, J-based configurational analysis, and ROE spectroscopic analysis. The structures of minutissamides A–D (1–4) were characterized by the presence of three nonstandard α-amino acid residues (two α,β-dehydro-α-aminobutyric acids and one N-methylated Asn) and one β-amino acid residue (2-hydroxy-3-amino-4-methyldodecanoic acid or 2-hydroxy-3-amino-4-methylhexadecanoic acid). Minutissamides A–D (1–4) exhibited antiproliferative activity against the HT-29 human colon cancer cell line with IC50 values of 2.0, 20.0, 11.8, and 22.7 μM, respectively.

Two polyketide metabolites, nhatrangins A (1) and B (2), were isolated from a Vietnamese collection of Lyngbya majuscula. These compounds are related to the aplysiatoxin series of metabolites, which have also been isolated from this species of marine cyanobacterium. The use of 900 MHz cryoprobe NMR allowed the elucidation of the 2D structure of 1 from approximately 0.3 mg of compound. LC-MS analysis was utilized to direct the isolation of additional material as well as the isolation of 2. Conformational analysis was completed using J-based coupling constant analysis and selective NOE experiments.

Eucapsitrione (1), an anthraquinone derivative with an indeno-anthracene-trione skeleton, was isolated from the cyanobacterium Eucapsis sp. (UTEX 1519) by bioassay-guided fractionation. The chemical structure was determined by analyzing MS and 1D and 2D NMR spectroscopic data. Eucapsitrione (1) showed anti-Mycobacterium tuberculosis activity in the microplate Alamar blue assay and low-oxygen-recovery assay with MIC values of 3.1 and 6.4 μM, respectively.

Material collected from a parkway in the city of Chicago afforded the isolation of a Nostoc species (UIC 10022A). The extract of this strain displayed significant inhibition of the 20S proteasome as well as antiproliferative activity against HT29, MCF7, NCI-H460, and SF268 cancer cell lines. A standardized dereplication protocol allowed for the rapid identification of three known (11−13) and nine new (1−9) chlorinated cylindrocyclophanes from less than 100 mg of organic extract. Scale-up isolation of 1−9 and 11−13 from a larger extract was guided by LC-UV-MS data. In addition, KBr enrichment of the culture media afforded the isolation of a brominated cylindrocyclophane (10). Biological evaluation of 1−5, 9, and 10−13 revealed a large range of activity against the 20S proteasome and allowed the determination of preliminary structure−activity relationships of the cylindrocyclophane pharmacophore.

Two cyclic peptides, scytonemides A (1) and B (2), were isolated from the cultured fresh water cyanobacterium Scytonema hofmannii (UTEX 1834) by bioassay-guided fractionation using a proteasome inhibition assay. The planar structures of the compounds were determined by a combination of MS and 1D and 2D NMR spectroscopy. The advanced Marfey’s method was used to determine the absolute configuration of both peptides. Scytonemide A possesses an unusual imino linkage, while scytonemide B is a depsipeptide containing 3-hydroxyoctanoic acid in the macrocycle. Both isolates were evaluated for their inhibition of the 20S proteasome, and scytonemide A displayed an IC50 value of 96 nM, while scytonemide B was inactive at 50 μM.

Four hapalindole-related alkaloids, namely fischambiguines A and B, ambiguine P, ambiguine Q nitrile as well as ambiguine G nitrile were identified from the cultured cyanobacterium Fischerella ambigua (UTEX 1903). The structures were determined by spectroscopic analysis including MS, 1D and 2D NMR and X-ray crystallography. The alkaloids possessed fused pentacyclic and hexacyclic carbon skeletons. Fischambiguine B displayed a strong inhibitory activity against Mycobacterium tuberculosis with an MIC value of 2 μM, with no detectable cytotoxicity in a Vero cell line.Four indole alkaloids were identified from the cultured cyanobacterium Fischerella ambigua (UTEX 1903). Fischambiguine B (2) displayed a strong inhibitory activity against Mycobacterium tuberculosis with an MIC value of 2 μM, with no detectable cytotoxicity in a Vero cell line.

Scytoscalarol (1), a antimicrobial sesterterpene bearing a guanidino group, was isolated from the cultured cyanobacterium Scytonema sp. (UTEX 1163) by bioassay-guided fractionation. The chemical structure was determined by spectroscopic analysis including MS and 1D and 2D NMR. Scytoscalarol (1) showed antimicrobial activities against Bacillus anthracis, Staphylococcus aureus, Escherichia coli, Candida albicans, and Mycobacterium tuberculosis with MIC values in the range from 2 to 110 μM.

Five new antibacterial ambiguine K−O isonitriles (1−5) and eight previously described indole alkaloids were isolated from the cultured cyanobacterium Fischerella ambigua (UTEX 1903) by bioassay-guided fractionation. The planar structures of the new compounds were determined by spectroscopic analysis including MS and 1D and 2D NMR. X-ray crystallography was used to determine the absolute stereoconfiguration of ambiguine K isonitrile. The isolates were evaluated for their antibacterial activities against a set of bacterial targets, including Mycobacterium tuberculosis and Bacillus anthracis. Ambiguine K and M isonitriles showed the most potent activity against M. tuberculosis, with MIC values of 6.6 and 7.5 μM, respectively. Ambiguine A isonitrile showed the most potent activity against B. anthracis, with a MIC of 1.0 μM.

•We isolated a cyclic hetapeptide, named microseiramide, from a freshwater cyanobacterium UIC 10445.•UIC 10445 was identified as a member of the recently described genus Microseira.•Microseiramide is the first cyclic peptide reported from a Microseira sp.Microseiramide (1), a cyclic heptapeptide, was isolated from a sample of the freshwater cyanobacterium Microseira sp. UIC 10445 collected in a shallow lake in Northern Indiana. Taxonomic identification of UIC 10445 was performed by a combination of morphological and phylogenetic characterization. Phylogenetic analysis revealed that UIC 10445 was a member of the recently described genus Microseira, which is phylogenetically distinct from the morphologically similar genera, Moorea and Lyngbya. The planar structure of microseiramide (1) was determined by extensive 1D and 2D NMR experiments as well as HRESIMS analysis. The absolute configurations of amino acid residues were determined using acid hydrolysis followed by the advanced Marfey’s analysis. Microseiramide (1) is the first cyclic peptide reported from a Microseira sp., and the structure of microseiramide (1) is distinct from the previously known metabolites from cyanobacteria of the genera Moorea and Lyngbya.Microseiramide, a cyclic heptapeptide, was isolated from a sample of the freshwater cyanobacterium Microseira sp. UIC 10445. It is the first cyclic peptide reported from a Microseira sp.Download full-size image