Enhancement of Cyclopamine via Conjugation with Nonmetabolic Sugars

The <i>Veratrum</i> alkaloid cyclopamine, an inhibitor of cancer stem cell growth, was used as a representative scaffold to evaluate the inhibitory impact of glycosylation with a group of nonmetabolic saccharides, such as d-threose. In a five-step divergent process, a 32-member glycoside library was created and assayed to determine that glycosides of such sugars notably improved the GI₅₀ value of cyclopamine while metabolic sugars, such as d-glucose, did not

Natural Product Disaccharide Engineering through Tandem Glycosyltransferase Catalysis Reversibility and Neoglycosylation

A two-step strategy for disaccharide modulation using vancomycin as a model is reported. The strategy relies upon a glycosyltransferase-catalyzed ‘reverse’ reaction to enable the facile attachment of an alkoxyamine-bearing sugar to the vancomycin core. Neoglycosylation of the corresponding aglycon led to a novel set of vancomycin 1,6-disaccharide variants. While the in vitro antibacterial properties of corresponding vancomycin 1,6-disaccharide analogs were equipotent to the parent antibiotic, the chemoenzymatic method presented is expected to be broadly applicable

Probing the Regiospecificity of Enzyme-Catalyzed Steroid Glycosylation

The potential of a uniquely permissive engineered glycosyltransferase (OleD ASP) as a catalyst for steroid glycosylation is highlighted. The ability of OleD ASP to glucosylate a range of cardenolides and bufadienolides was assessed using a rapid LC-UV/MS-SPE-NMR analytical platform. While a bias toward OleD-catalyzed C3 monoglucosylation was observed, subtle alterations of the steroidal architecture, in some cases, invoked diglucosylation or, in one case (digoxigenin), C12 glucosylation. This latter case represents the first, and highly efficient, synthesis of digoxigenin 12-<i>O</i>-β-d-glucoside

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

Antibacterial Muraymycins from Mutant Strains of <i>Streptomyces</i> sp. NRRL 30471

Muraymycins are nucleoside antibiotics isolated from <i>Streptomyces</i> sp. NRRL 30471 and several mutant strains thereof that were generated by random, chemical mutagenesis. Reinvestigation of two mutant strains using new media conditions led to the isolation of three new muraymycin congeners, named B8, B9, and C6 (<b>1</b>–<b>3</b>), as well as a known muraymycin, C1. Structures of the compounds were elucidated by HRMS and 1D and 2D NMR spectroscopic analyses. Complete 2D NMR assignments for the known muraymycin C1 are also provided for the first time. Compounds <b>1</b> and <b>2</b>, which differ from other muraymycins by having an elongated, terminally branched fatty acid side chain, had picomolar IC₅₀ values against <i>Staphylococcus aureus</i> and <i>Aquifex aeolicus</i> MraY and showed good antibacterial activity against <i>S. aureus</i> (MIC = 2 and 6 μg/mL, respectively) and <i>Escherichia coli</i> Δ<i>tolC</i> (MIC = 4 and 2 μg/mL, respectively). Compound <b>3</b>, which is characterized by an <i>N</i>-acetyl modification of the primary amine of the dissacharide core that is shared among nearly all of the reported muraymycin congeners, greatly reduced its inhibitory and antibacterial activity compared to nonacylated muraymycin C1, which possibly indicates this modification is used for self-resistance

Synthesis and Antibacterial Activity of Doxycycline Neoglycosides

A set of 37 doxycycline neoglycosides were prepared, mediated via a C-9 alkoxyamino-glycyl-based spacer reminiscent of that of tigecycline. Subsequent <i>in vitro</i> antibacterial assays against representative drug-resistant Gram negative and Gram positive strains revealed a sugar-dependent activity profile and one doxycycline neoglycoside, the 2′-amino-α-d-glucoside conjugate, to rival that of the parent pharmacophore. In contrast, the representative tetracycline-susceptible strain <i>E. coli</i> 25922 was found to be relatively responsive to a range of doxycycline neoglycosides. This study also extends the use of aminosugars in the context of neoglycosylation via a simple two-step strategy anticipated to be broadly applicable for neoglycorandomization

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

A Diastereoselective Oxa-Pictet–Spengler-Based Strategy for (+)-Frenolicin B and <i>epi</i>-(+)-Frenolicin B Synthesis

An efficient diastereoselective oxa-Pictet–Spengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of the reaction was demonstrated in the context of both the total synthesis of naturally occurring pyranonaphthoquinones (+)-frenolicin B and <i>epi</i>-(+)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such, offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs

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

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