5 research outputs found
Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide
It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue
Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide
It
was by way of total synthesis that the issues concerning the
stereostructure of leiodermatolide (<b>1</b>) have recently
been solved; with the target now being unambiguously defined, the
mission of synthesis changes as to secure a meaningful supply of this
exceedingly scarce natural product derived from a deep-sea sponge.
To this end, a scalable route of 19 steps (longest linear sequence)
has been developed, which features a catalytic asymmetric propargylation
of a highly enolizable β-keto-lactone, a ring closing alkyne
metathesis and a modified Stille coupling as the key transformations.
Deliberate digression from this robust blueprint brought a first set
of analogues into reach, which allowed the lead qualities of <b>1</b> to be assessed. The acquired biodata show that <b>1</b> is a potent cytotoxin in human tumor cell proliferation assays,
distinguished by GI<sub>50</sub> values in the ≤3 nM range
even for cell lines expressing the Pgp efflux transporter. Studies
with human U2OS cells revealed that <b>1</b> causes mitotic
arrest, micronucleus induction, centrosome amplification and tubulin
disruption, even though no evidence for direct tubulin binding has
been found in cell-free assays; moreover, the compound does not seem
to act through kinase inhibition. Indirect evidence points at centrosome
declustering as a possible mechanism of action, which provides a potentially
rewarding outlook in that centrosome declustering agents hold promise
of being inherently selective for malignant over healthy human tissue
Recommended from our members
Receptor-Mediated Delivery of CRISPR-Cas9 Endonuclease for Cell-Type-Specific Gene Editing.
CRISPR-Cas RNA-guided endonucleases hold great promise for disrupting or correcting genomic sequences through site-specific DNA cleavage and repair. However, the lack of methods for cell- and tissue-selective delivery currently limits both research and clinical uses of these enzymes. We report the design and in vitro evaluation of S. pyogenes Cas9 proteins harboring asialoglycoprotein receptor ligands (ASGPrL). In particular, we demonstrate that the resulting ribonucleoproteins (Cas9-ASGPrL RNP) can be engineered to be preferentially internalized into cells expressing the corresponding receptor on their surface. Uptake of such fluorescently labeled proteins in liver-derived cell lines HEPG2 (ASGPr+) and SKHEP (control; diminished ASGPr) was studied by live cell imaging and demonstrates increased accumulation of Cas9-ASGPrL RNP in HEPG2 cells as a result of effective ASGPr-mediated endocytosis. When uptake occurred in the presence of a peptide with endosomolytic properties, we observed receptor-facilitated and cell-type specific gene editing that did not rely on electroporation or the use of transfection reagents. Overall, these in vitro results validate the receptor-mediated delivery of genome-editing enzymes as an approach for cell-selective gene editing and provide a framework for future potential applications to hepatoselective gene editing in vivo
Identification of Multiple 5‑HT<sub>4</sub> Partial Agonist Clinical Candidates for the Treatment of Alzheimer’s Disease
The cognitive impairments observed in Alzheimer’s
disease (AD) are in part a consequence of reduced acetylcholine (ACh)
levels resulting from a loss of cholinergic neurons. Preclinically,
serotonin 4 receptor (5-HT<sub>4</sub>) agonists are reported to modulate
cholinergic function and therefore may provide a new mechanistic approach
for treating cognitive deficits associated with AD. Herein we communicate
the design and synthesis of potent, selective, and brain penetrant
5-HT<sub>4</sub> agonists. The overall goal of the medicinal chemistry
strategy was identification of structurally diverse clinical candidates
with varying intrinsic activities. The exposure–response relationships
between binding affinity, intrinsic activity, receptor occupancy,
drug exposure, and pharmacodynamic activity in relevant preclinical
models of AD were utilized as key selection criteria for advancing
compounds. On the basis of their excellent balance of pharmacokinetic
attributes and safety, two lead 5-HT<sub>4</sub> partial agonist candidates <b>2d</b> and <b>3</b> were chosen for clinical development