The Identification of Perillyl Alcohol Glycosides with Improved Antiproliferative Activity

A facile route to perillyl alcohol (POH) differential glycosylation and the corresponding synthesis of a set of 34 POH glycosides is reported. Subsequent in vitro studies revealed a sugar dependent antiproliferative activity and the inhibition of S6 ribosomal protein phosphorylation as a putative mechanism of representative POH glycosides. The most active glycoside from this cumulative study (4′-azido-d-glucoside, <b>PG9</b>) represents one of the most cytotoxic POH analogues reported to date

Influence of Sugar Amine Regiochemistry on Digitoxigenin Neoglycoside Anticancer Activity

The synthesis of a set of digitoxigenin neogluco/xylosides and corresponding study of their anticancer SAR revealed sugar amine regiochemistry has a dramatic effect upon activity. Specifically, this study noted sugar 3-amino followed by 4-amino-substitution to be most advantageous where the solvent accessibility of the appended amine within neoglycoside-Na⁺,K⁺-ATPase docked models correlated with increased anticancer potency. This study presents a preliminary model for potential further warhead optimization in the context of antibody-directed steroidal glycosides and extends the demonstrated compatibility of aminosugars in the context of neoglycosylation

Herbimycins D–F, Ansamycin Analogues from <i>Streptomyce</i>s sp. RM-7-15

Bacterial strains belonging to the class actinomycetes were isolated from the soil near a thermal vent of the Ruth Mullins coal fire (Appalachian Mountains of eastern Kentucky). High-resolution electrospray ionization mass spectrometry and ultraviolet absorption profiles of metabolites from one of the isolates (<i>Streptomyces</i> sp. RM-7-15) revealed the presence of a unique set of metabolites ultimately determined to be herbimycins D–F (<b>1</b>–<b>3</b>). In addition, herbimycin A (<b>4</b>), dihydroherbimycin A (TAN 420E) (<b>7</b>), and the structurally distinct antibiotic bicycylomycin were isolated from the crude extract of <i>Streptomyces</i> sp. RM-7-15. Herbimycins A and D–F (<b>1</b>–<b>3</b>) displayed comparable binding affinities to the Hsp90α. While the new analogues were found to be inactive in cancer cell cytotoxicity and antimicrobial assays, they may offer new insights in the context of nontoxic ansamycin-based Hsp90 inhibitors for the treatment of neurodegenerative disease

Antibacterial and Cytotoxic Actinomycins Y₆–Y₉ and Zp from <i>Streptomyces</i> sp. Strain Gö-GS12

Four new Y-type actinomycin analogues named Y₆–Y₉ (<b>1</b>–<b>4</b>) were isolated and characterized from the scale-up fermentation of the <i>Streptomyces</i> sp. strain Gö-GS12, as well as actinomycin Zp (<b>5</b>), which was, for the first time, isolated as a natural product. Structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and HRMS. The 4-hydroxythreonine on the β-ring of <b>1</b> uniquely undergoes both a rearrangement by a 2-fold acyl shift and an additional ring closure with the amino group of the phenoxazinone chromophore, and the α-rings of <b>4</b> and <b>5</b> contain a rare 5-methyl proline. Compounds <b>2</b>–<b>5</b> showed potent antibacterial activities against Gram-positive bacteria that correlated with cytotoxicity against representative human cell lines. The combination of a β-ring rearrangement and additional ring closure in <b>1</b> rendered this actinomycin significantly less potent relative to the nonrearranged comparator actinomycin Y₅ and other actinomycins

Frenolicins C–G, Pyranonaphthoquinones from <i>Streptomyces</i> sp. RM-4-15

Appalachian active coal fire sites were selected for the isolation of bacterial strains belonging to the class actinobacteria. A comparison of high-resolution electrospray ionization mass spectrometry (HRESIMS) and ultraviolet (UV) absorption profiles from isolate extracts to natural product databases suggested <i>Streptomyces</i> sp. RM-4-15 to produce unique metabolites. Four new pyranonaphthoquinones, frenolicins C–F (<b>1</b>–<b>4</b>), along with three known analogues, frenolicin (<b>6</b>), frenolicin B (<b>7</b>), and UCF76-A (<b>8</b>), were isolated from the fermentation of this strain. An additional new analogue, frenolicin G (<b>5</b>), along with two known compounds, deoxyfrenolicin (<b>9</b>) and UCF 13 (<b>10</b>), were isolated from the fermentation supplied with 18 mg/L of scandium chloride, the first example, to the best of our knowledge, wherein scandium chloride supplementation led to the confirmed production of new bacterial secondary metabolites. Structures <b>1</b>–<b>5</b> were elucidated on the basis of spectral analysis and chemical modification. While frenolicins are best known for their anticoccidial activity, the current study revealed compounds <b>6</b>–<b>9</b> to exhibit moderate cytotoxicity against the human lung carcinoma cell line (A549) and thereby extends the anticancer SAR for this privileged scaffold

Ruthmycin, a New Tetracyclic Polyketide from <i>Streptomyces</i> sp. RM‑4‑15

The isolation and structural elucidation of a new tetracyclic polyketide (ruthmycin) from <i>Streptomyces</i> sp. RM-4-15, a bacteria isolated near thermal vents from the Ruth Mullins underground coal mine fire in eastern Kentucky, is reported. In comparison to the well-established frenolicin core scaffold, ruthmycin possesses an unprecedented signature C₃ bridge and a corresponding fused six member ring. Preliminary in vitro antibacterial, anticancer, and antifungal assays revealed ruthmycin to display moderate antifungal activity

Identification of Neuroprotective Spoxazomicin and Oxachelin Glycosides via Chemoenzymatic Glycosyl-Scanning

The assessment of glycosyl-scanning to expand the molecular and functional diversity of metabolites from the underground coal mine fire-associated <i>Streptomyces</i> sp. RM-14-6 is reported. Using the engineered glycosyltransferase OleD Loki and a 2-chloro-4-nitrophenylglycoside-based screen, six metabolites were identified as substrates of OleD Loki, from which 12 corresponding metabolite glycosides were produced and characterized. This study highlights the first application of the 2-chloro-4-nitrophenylglycoside-based screen toward an unbiased set of unique microbial natural products and the first reported application of the 2-chloro-4-nitrophenylglycoside-based transglycosylation reaction for the corresponding preparative synthesis of target glycosides. Bioactivity analysis (including antibacterial, antifungal, anticancer, and EtOH damage neuroprotection assays) revealed glycosylation to attenuate the neuroprotective potency of <b>4</b>, while glycosylation of the structurally related inactive spoxazomicin C (<b>3</b>) remarkably invoked neuroprotective activity

Bi- and Tetracyclic Spirotetronates from the Coal Mine Fire Isolate <i>Streptomyces</i> sp. LC-6‑2

The structures of 12 new “enantiomeric”-like abyssomicin metabolites (abyssomicins M–X) from <i>Streptomyces</i> sp. LC-6-2 are reported. Of this set, the abyssomicin W (<b>11</b>) contains an unprecedented 8/6/6/6 tetracyclic core, while the bicyclic abyssomicin X (<b>12</b>) represents the first reported naturally occurring linear spirotetronate. Metabolite structures were determined based on spectroscopic data and X-ray crystallography, and <i>Streptomyces</i> sp. LC-6-2 genome sequencing also revealed the corresponding putative biosynthetic gene cluster

Spoxazomicin D and Oxachelin C, Potent Neuroprotective Carboxamides from the Appalachian Coal Fire-Associated Isolate <i>Streptomyces</i> sp. RM-14‑6

The isolation and structure elucidation of six new bacterial metabolites [spoxazomicin D (<b>2</b>), oxachelins B and C (<b>4</b>, <b>5</b>), and carboxamides <b>6</b>–<b>8</b>] and 11 previously reported bacterial metabolites (<b>1</b>, <b>3</b>, <b>9</b>–<b>12a</b>, and <b>14</b>–<b>18</b>) from <i>Streptomyces</i> sp. RM-14-6 is reported. Structures were elucidated on the basis of comprehensive 1D and 2D NMR and mass spectrometry data analysis, along with direct comparison to synthetic standards for <b>2</b>, <b>11</b>, and <b>12a</b>,<b>b</b>. Complete 2D NMR assignments for the known metabolites lenoremycin (<b>9</b>) and lenoremycin sodium salt (<b>10</b>) were also provided for the first time. Comparative analysis also provided the basis for structural revision of several previously reported putative aziridine-containing compounds [exemplified by madurastatins A1, B1, C1 (also known as MBJ-0034), and MBJ-0035] as phenol-dihydrooxazoles. Bioactivity analysis [including antibacterial, antifungal, cancer cell line cytotoxicity, unfolded protein response (UPR) modulation, and EtOH damage neuroprotection] revealed <b>2</b> and <b>5</b> as potent neuroprotectives and lenoremycin (<b>9</b>) and its sodium salt (<b>10</b>) as potent UPR modulators, highlighting new functions for phenol-oxazolines/salicylates and polyether pharmacophores

Terfestatins B and C, New <i>p</i>‑Terphenyl Glycosides Produced by <i>Streptomyces</i> sp. RM-5–8

Terfestatins B (<b>1</b>) and C (<b>2</b>), new <i>p</i>-terphenyls bearing a novel unsaturated hexuronic acid (4-deoxy-α-l-<i>threo</i>-hex-4-enopyranuronate), a unique β-d-glycosyl ester of 5-isoprenylindole-3-carboxylate (<b>3</b>) and the same rare sugar, and two new hygromycin precursors, were characterized as metabolites of the coal mine fire isolate <i>Streptomyces</i> sp. RM-5–8. EtOH damage neuroprotection assays using rat hippocampal-derived primary cell cultures with <b>1</b>, <b>2</b>, <b>3</b> and echoside B (a terfestatin C-3′-β-d-glucuronide from <i>Streptomyces</i> sp. RM-5–8) revealed <b>1</b> as potently neuroprotective, highlighting a new potential application of the terfestatin scaffold