Englerins A and B are guaiane sesquiterpenes that were isolated from the bark of Phyllanthus engleri, a plant indigenous to east Africa. The englerins consist of a 5-6-5 fused tricyclic structure with an ether bridge and two ester-bearing stereogenic centers, including a highly unusual glycolate residue. Englerin A is a potent and selective inhibitor of the growth of six human renal cancer cell lines. We report herein an efficient, eight-step synthesis of englerin A that leverages simple carbonyl-enabled carbon-carbon bond formations. Our route is amenable to the production of a diverse series of analogues for structure-function studies and determination of the mode of action of these natural products.
The number of renal cancers has increased over the last ten years and patient
survival in advanced stages remains very poor. Therefore, new therapeutic
approaches for renal cancer are essential. Englerin A is a natural product with
a very potent and selective cytotoxicity against renal cancer cells. This makes
it a promising drug candidate that may improve current treatment standards for
patients with renal cancers in all stages. However, little is known about
englerin A's mode of action in targeting specifically renal cancer cells.
Our study is the first to investigate the biological mechanism of englerin A
action in detail. We report that englerin A is specific for renal tumor cells
and does not affect normal kidney cells. We find that englerin A treatment
induces necrotic cell death in renal cancer cells but not in normal kidney
cells. We further show that autophagic and pyroptotic proteins are unaffected by
the compound and that necrotic signaling in these cells coincided with
production of reactive oxygen species and calcium influx into the cytoplasm. As
the first study to analyze the biological effects of englerin A, our work
provides an important basis for the evaluation and validation of the
compound's use as an anti-tumor drug. It also provides a context in which
to identify the specific target or targets of englerin A in renal cancer
cells.
Angularly substituted
trans-fused hydroindanes are now accessible
by the direct and convergent union of trimethylsilyl (TMS)-alkynes
with 4-hydroxy-1,6-enynes by a process that forges three C–C
bonds, one C–H bond, and two new stereocenters. The annulation
is proposed to proceed by initial formation of a Ti–alkyne
complex (with a TMS-alkyne) followed by regioselective alkoxide-directed
coupling with the enyne, stereoselective intramolecular cycloaddition,
elimination of phenoxide, 1,3-metallotropic shift, and stereoselective
protonation of the penultimate allylic organometallic intermediate.
Several examples are given to demonstrate the compatibility of this
reaction with substrates bearing aromatic and aliphatic substituents,
and an empirical model is presented to accompany the stereochemical
observations.
Finite element analysis was used to assess whether the postorbital septum plays a meaningful biomechanical role as a structural support for the circumorbital region in a species of macaque, an anthropoid primate. A finite element model was constructed of a Macaca fascicularis cranium that was subsequently modified to create a second model in which the septum was removed bilaterally. The models were subjected to forces and constraints simulating a molar bite, and resulting strains and displacements were recorded. Strain magnitudes at selected locations on the models were typically lower or unchanged in the model lacking septae, which would seem to be contrary to expectations. However, more broadly, relative to the model containing septae, the model without septae exhibited a mosaic pattern of strain increases and decreases in the circumorbital region. The model lacking septae also exhibited more asymmetric displacements in the orbital region, although not in precisely the manner predicted by prior experimental studies. Overall, the mechanical impact of the postorbital septum is minimal in macaques. These results, when considered along with those of prior experimental studies, suggest that either the postorbital septum in anthropoids did not evolve for mechanical reasons, or, if it did, it no longer plays such a role in extant taxa.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations –citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.