B(C\u3csub\u3e6\u3c/sub\u3eF\u3csub\u3e5\u3c/sub\u3e)\u3csub\u3e3\u3c/sub\u3e-promoted tandem silylation and intramolecular hydrosilylation: diastereoselective synthesis of oxasilinanes and oxasilepanes

B(C6F5)3 promotes regio- and stereoselective cyclizations of unsaturated alkoxysilanes to generate oxasilinanes and oxasilepanes. The same products are available directly from alkenols via tandem silylation and hydrosilylation

Quorum Sensing in \u3ci\u3eCandida albicans\u3c/i\u3e: Probing Farnesol’s Mode of Action with 40 Natural and Synthetic Farnesol Analogs

The dimorphic fungus Candida albicans produces extracellular farnesol (3,7, 11-trimethyl-2,6,10-dodecatriene- 1-ol) which acts as a quorum-sensing molecule (QSM) to suppress filamentation. Of four possible geometric isomers of farnesol, only the E,E isomer possesses QSM activity. We tested 40 natural and synthetic analogs of farnesol for their activity in an N-acetylglucosamine-induced differentiation assay for germ tube formation (GTF). Modified structural features include the head group, chain length, presence or absence of the three double bonds, substitution of a backbone carbon by S, O, N, and Se heteroatoms, presence or absence of a 3-methyl branch, and the bulkiness of the hydrophobic tail. Of the 40 compounds, 22 showed QSM activity by their ability to reduce GTF by 50%. However, even the most active of the analogs tested had only 7.3% of the activity of E,E-farnesol. Structure-activity relationships were examined in terms of the likely presence in C. albicans of a farnesol binding receptor protein. Includes supplemental material

Investigation of quorum sensing in Candida albicans

The dimorphic fungus Candida albicans produces extracellular farnesol which acts as a quorum-sensing molecule (QSM) to suppress filamentation. Of four possible geometric isomers of farnesol, only the E,E isomer possesses QSM activity. We tested number of natural and synthetic analogs of farnesol for their activity in an N-acetylglucosamine-induced differentiation assay for germ tube formation (GTF). Modified structural features include the nature of the head group, chain length, presence or absence of the three double bonds, substitution of a backbone carbon by S, O, N, and Se heteroatoms, presence or absence of a 3-methyl branch, as well as the bulkiness and the hydrophobic tail. In order to elucidate localization a putative receptor we prepared ten polyenes typified by 3,7,11-trimethyl-2,4,6,8,10-dodecapentenaldehyde oxime. Four of the ten analogs display strong quorum-sensing activity in the human pathogen Candida albicans, also they are fluorescent. Therefore oxime anti-4 is demonstrated to be useful for confocal fluorescence microscopic imaging of fungal cells. Also, we have investigated of a series of farnesol analogs replacing the primary alcohol head group with several classes of heterocycles. High levels of quorum-sensing activity were associated with several types of heterocycles. Two non toxic analogs were tested in C. albicans inoculated immune-challenged mice. One of the two analogs has been shown to perfectly emulate farnesol in vivo behavior, which unfortunately includes an increase of C. Albicans virulence in the mice. In an attempt to isolate putative farnesol binding receptor we synthesized of affinity media designed to isolate a putative farnesol receptor or binding protein in C. albicans. The approach rests on a new class of farnesol analogs, which maintain the acidic head group and farnesyl-like backbone known from our earlier studies to be necessary for quorum sensing, but which also allow for covalent chemical linkage of the head group to an affinity support. In preliminary results, affinity chromatography of the total protein extract of C. albicans resulted in selective retention of a handful of proteins. Mass spectrometry of some of eluted proteins reveals two matches against known fungal proteins

Biologically Active Fluorescent Farnesol Analogs

We describe ten polyene analogs of farnesol, typified by 3,7,11-trimethyl-2,4,6,8,10-dodecapentenaldehyde oxime, which preserve the length, cross-section, and approximate hydrophobicity of farnesol. Four of the ten display strong quorum- sensing activity in the human pathogen Candida albicans, with IC50 values for inhibition of germ-tube formation as low as 10 μM. The polyenes display absorption maxima between 320 and 380 nm, with the extinction coefficients for the oximes approaching 100,000. All but two of the analogs are fluorescent, with excitation maxima varying over the range of 320–370 nm. Oxime anti-4, which can undergo fluorescence excitation at wavelengths beyond 400 nm, is demonstrated to be useful for confocal fluorescence microscopic imaging of fungal cells. The farnesol analogs are also expected to be useful for detection of farnesol binding proteins and in determination of farnesol pharmacokinetics. Includes Supplemental Data not published with the printed journal edition, and previously available only online

Influence of heterocyclic and oxime-containing farnesol analogs on quorum sensing and pathogenicity in \u3ci\u3eCandida albicans\u3c/i\u3e

A series of synthetic molecules combining a geranyl backbone with a heterocyclic or oxime head group are quorum-sensing molecules that block the yeast to mycelium transition in the dimorphic fungus Candida albicans. A number of the analogs have an IC50 ≤ 10 μM, a level of potency essentially identical to the natural quorum sensing signal, the sesquiterpene farnesol. Two of the most potent analogs, neither toxic toward healthy mice, display remarkably different effects when co-administered with C. albicans. While neither offers protection from candidiasis, one analog mimics farnesol in acting as a virulence factor, whereas the other has no effect. The results offer the first example of highly potent synthetic fungal quorum-sensing molecules, and provide the first evidence for the ability to decouple quorum sensing and virulence

Spin–Lattice Relaxation of Hyperpolarized Metronidazole in Signal Amplification by Reversible Exchange in Micro-Tesla Fields

Simultaneous reversible chemical exchange of <i>para</i>-hydrogen and to-be-hyperpolarized substrate on metal centers enables spontaneous transfer of spin order from <i>para</i>-hydrogen singlet to nuclear spins of the substrate. When performed at a sub-micro-tesla magnetic field, this technique of NMR signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH). SABRE-SHEATH has been shown to hyperpolarize nitrogen-15 sites of a wide range of biologically interesting molecules to a high polarization level (<i>P</i> > 20%) in 1 min. Here, we report on a systematic study of ¹H, ¹³C, and ¹⁵N spin–lattice relaxation (<i>T</i>₁) of metronidazole-¹³C₂-¹⁵N₂ in the SABRE-SHEATH hyperpolarization process. In the micro-tesla range, we find that all ¹H, ¹³C, and ¹⁵N spins studied share approximately the same <i>T</i>₁ values (ca. 4 s under the conditions studied) because of mixing of their Zeeman levels, which is consistent with the model of relayed SABRE-SHEATH effect. These <i>T</i>₁ values are significantly lower than those at a higher magnetic field (i.e. the Earth’s magnetic field and above), which exceed 3 min in some cases. Moreover, these relatively short <i>T</i>₁ values observed below 1 μT limit the polarization build-up process of SABRE-SHEATH, thereby limiting the maximum attainable ¹⁵N polarization. The relatively short <i>T</i>₁ values observed below 1 μT are primarily caused by intermolecular interactions with quadrupolar iridium centers or dihydride protons of the employed polarization transfer catalyst, whereas intramolecular spin–spin interactions with ¹⁴N quadrupolar centers have a significantly smaller contribution. The presented experimental results and their analysis will be beneficial for more rational design of SABRE-SHEATH (i) polarization transfer catalysts and (ii) hyperpolarized molecular probes in the context of biomedical imaging and other applications

Parahydrogen-Induced Polarization with a Rh-Based Monodentate Ligand in Water

Reported here is a water-soluble Rh­(I)-based catalyst for performing parahydrogen-induced polarization (PHIP). The [Rh­(I)­(norbornadiene)­(THP)₂]⁺[BF₄]⁻ catalyst utilizes the monodentate phosphine ligand tris­(hydroxymethyl)­phosphine (THP). The monodentate PHIP catalyst is less susceptible to oxygenation by air and the THP ligand is significantly less expensive than bidentate water-soluble PHIP ligands. In situ PHIP detection with this monodentate Rh­(I)-based catalyst in water yielded 12% ¹³C polarization for the parahydrogen addition product, 2-hydroxyethyl 1-¹³C-propionate-d_2,3,3 (HEP), with a ¹³C <i>T</i>₁ relaxation of 108 s at 0.0475 T. PHIP polarization yields were high, reflecting efficient hydrogenation even under conditions of high content of the oxidized phosphine form of the THP ligand