5 research outputs found
Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp<sup>3</sup>) Boronate Building Blocks
Efficient access to chiral C(sp<sup>3</sup>) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp<sup>3</sup>) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable α-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp<sup>3</sup>-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp<sup>3</sup>) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis
C2′-OH of Amphotericin B Plays an Important Role in Binding the Primary Sterol of Human Cells but Not Yeast Cells
Amphotericin B (AmB) is a clinically
vital antimycotic but is limited
by its severe toxicity. Binding ergosterol, independent of channel
formation, is the primary mechanism by which AmB kills yeast, and
binding cholesterol may primarily account for toxicity to human cells.
The leading structural model predicts that the C2′ hydroxyl
group on the mycosamine appendage is critical for binding both sterols.
To test this, the C2′-OH was synthetically deleted, and the
sterol binding capacity of the resulting derivative, C2′deOAmB,
was directly characterized via isothermal titration calorimetry. Surprisingly,
C2′deOAmB binds ergosterol and, within the limits of detection
of this experiment, does not bind cholesterol. Moreover, C2′deOAmB
is nearly equipotent to AmB against yeast but, within the limits of
detection of our assays, is nontoxic to human cells in vitro. Thus,
the leading structural model for AmB/sterol binding interactions is
incorrect, and C2′deOAmB is an exceptionally promising new
antifungal agent
C2′-OH of Amphotericin B Plays an Important Role in Binding the Primary Sterol of Human Cells but Not Yeast Cells
Amphotericin B (AmB) is a clinically
vital antimycotic but is limited
by its severe toxicity. Binding ergosterol, independent of channel
formation, is the primary mechanism by which AmB kills yeast, and
binding cholesterol may primarily account for toxicity to human cells.
The leading structural model predicts that the C2′ hydroxyl
group on the mycosamine appendage is critical for binding both sterols.
To test this, the C2′-OH was synthetically deleted, and the
sterol binding capacity of the resulting derivative, C2′deOAmB,
was directly characterized via isothermal titration calorimetry. Surprisingly,
C2′deOAmB binds ergosterol and, within the limits of detection
of this experiment, does not bind cholesterol. Moreover, C2′deOAmB
is nearly equipotent to AmB against yeast but, within the limits of
detection of our assays, is nontoxic to human cells in vitro. Thus,
the leading structural model for AmB/sterol binding interactions is
incorrect, and C2′deOAmB is an exceptionally promising new
antifungal agent
Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel
Deficiencies
of protein ion channels underlie many currently incurable human diseases.
Robust networks of pumps and channels are usually responsible for
the directional movement of specific ions in organisms ranging from
microbes to humans. We thus questioned whether minimally selective
small molecule mimics of missing protein channels might be capable
of collaborating with the corresponding protein ion pumps to restore
physiology. Here we report vigorous and sustainable restoration of
yeast cell growth by replacing missing protein ion transporters with
imperfect small molecule mimics. We further provide evidence that
this tolerance for imperfect mimicry is attributable to collaboration
between the channel-forming small molecule and protein ion pumps.
These results illuminate a mechanistic framework for pursuing small
molecule replacements for deficient protein ion channels that underlie
a range of challenging human diseases
C3-OH of Amphotericin B Plays an Important Role in Ion Conductance
Amphotericin
B (AmB) is the archetype for small molecules that
form ion channels in living systems and has recently been shown to
replace a missing protein ion transporter and thereby restore physiology
in yeast. Molecular modeling studies predict that AmB self-assembles
in lipid membranes with the polyol region lining a channel interior
that funnels to its narrowest region at the C3-hydroxyl group. This
model predicts that modification of this functional group would alter
conductance of the AmB ion channel. To test this hypothesis, the C3-hydroxyl
group was synthetically deleted, and the resulting derivative, C3deoxyAmB
(C3deOAmB), was characterized using multidimensional NMR experiments
and single ion channel electrophysiology recordings. C3deOAmB possesses
the same macrocycle conformation as AmB and retains the capacity to
form transmembrane ion channels, yet the conductance of the C3deOAmB
channels is 3-fold lower than that of AmB channels. Thus, the C3-hydroxyl
group plays an important role in AmB ion channel conductance, and
synthetic modifications at this position may provide an opportunity
for further tuning of channel functions