3 research outputs found
Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (−)-Frondosin B and (+)-Frondosin A
The asymmetric total
syntheses of the natural products (+)- and
(−)-frondosin B and (+)-frondosin A are reported based on a
diastereoselective cycloaddition between tetrabromocyclopropene and
an annulated furan to provide a highly functionalized common building
block. The bridged bicyclic intermediate could be stereo- and chemoselectively
manipulated to produce the two structurally distinct members of the
frondosins. Both syntheses feature regioselective palladium-coupling
reactions and an unprecedented phosphine-mediated ether bridge cleavage.
Surprisingly, the planned enantioselective synthesis of frondosin
B led to the opposite epimer of the natural product, suggesting an
unusual late stage stereoinversion at C8. Frondosin A, but not frondosin
B, was shown to have selective antiproliferative activity against
several B-cell lines
Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (−)-Frondosin B and (+)-Frondosin A
The asymmetric total
syntheses of the natural products (+)- and
(−)-frondosin B and (+)-frondosin A are reported based on a
diastereoselective cycloaddition between tetrabromocyclopropene and
an annulated furan to provide a highly functionalized common building
block. The bridged bicyclic intermediate could be stereo- and chemoselectively
manipulated to produce the two structurally distinct members of the
frondosins. Both syntheses feature regioselective palladium-coupling
reactions and an unprecedented phosphine-mediated ether bridge cleavage.
Surprisingly, the planned enantioselective synthesis of frondosin
B led to the opposite epimer of the natural product, suggesting an
unusual late stage stereoinversion at C8. Frondosin A, but not frondosin
B, was shown to have selective antiproliferative activity against
several B-cell lines
Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism
Butyrophilin 3A1
(BTN3A1) binds small phosphorus-containing molecules,
which initiates transmembrane signaling and activates butyrophilin-responsive
cells. We synthesized several phosphinophosphonates and their corresponding
tris-pivaloyloxymethyl (tris-POM) prodrugs and examined their effects
on BTN3A1. An analog of (<i>E</i>)-4-hydroxy-3-methyl-but-2-enyl
diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which
was enthalpy-driven. Docking studies revealed binding to the basic
surface pocket and interactions between the allylic hydroxyl group
and the BTN3A1 backbone. The phosphinophosphonate stimulated proliferation
of Vγ9Vδ2 T cells with moderate activity (EC<sub>50</sub> = 26 μM). Cellular potency was enhanced >600-fold in the
tris-POM
prodrug (EC<sub>50</sub> = 0.041 μM). The novel prodrug also
induced T cell mediated leukemia cell lysis. Analysis of dose–response
data reveals HMBPP-induced Hill coefficients of 0.69 for target cell
lysis and 0.68 in interferon secretion. Together, tris-POM prodrugs
enhance the cellular activity of phosphinophosphonates, reveal structure–activity
relationships of butyrophilin ligands, and support a negatively cooperative
model of cellular butyrophilin activation