Phosphorus, Sulfur, and Silicon and the Related Elements, 2014
ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and have demonstrated excellent gains in potency through delivery of the phosphoantigen to the intracellular domain of BTN3A1.
Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...
Phosphorus, Sulfur, and Silicon and the Related Elements, 1990
The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by usin... more The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by using lipid p-nitrophenyl esters and thiophospholipids as substrates. The rate of CEase-catalyzed hydrolyses of p-nitrophenyl esters is highest for substrates that have fatty acyl chains of intermediate length, while solvent isotope effects decrease with increasing chain length. Nucleophilic trapping experiments indicate that kcat for these substrates is
Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Mies... more Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Miescher ketone is described. This synthetic sequence provides convenient access to the natural enantiomers and, based on comparison of the optical rotation of synthetic avarol dimethyl ether with literature data, affords material of significantly higher optical rotation than a natural source. Similar synthetic strategies have been used to obtain several related compounds, including a decalin bearing an exocyclic olefin and a highly substituted cyclohexane, that can be viewed as hybrids of the trans-fused avarol and cis-fused arenarol skeletons.
Phosphorus, Sulfur, and Silicon and the Related Elements, 2002
ABSTRACT Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the... more ABSTRACT Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the corresponding nucleoside aldehydes and tested for their ability to serve as substrates for nucleotide monophosphate kinase and for their toxicity to K562 leukemia cells.
Phosphorus, Sulfur, and Silicon and the Related Elements, 2014
ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and have demonstrated excellent gains in potency through delivery of the phosphoantigen to the intracellular domain of BTN3A1.
Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...
Phosphorus, Sulfur, and Silicon and the Related Elements, 2014
ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and have demonstrated excellent gains in potency through delivery of the phosphoantigen to the intracellular domain of BTN3A1.
Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...
Phosphorus, Sulfur, and Silicon and the Related Elements, 1990
The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by usin... more The catalytic mechanism of bovine pancreatic cholesterol esterase (CEase) has been probed by using lipid p-nitrophenyl esters and thiophospholipids as substrates. The rate of CEase-catalyzed hydrolyses of p-nitrophenyl esters is highest for substrates that have fatty acyl chains of intermediate length, while solvent isotope effects decrease with increasing chain length. Nucleophilic trapping experiments indicate that kcat for these substrates is
Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Mies... more Synthesis of the rearranged drimane sesquiterpenoids (+)-avarol and (+)-avarone from Wieland-Miescher ketone is described. This synthetic sequence provides convenient access to the natural enantiomers and, based on comparison of the optical rotation of synthetic avarol dimethyl ether with literature data, affords material of significantly higher optical rotation than a natural source. Similar synthetic strategies have been used to obtain several related compounds, including a decalin bearing an exocyclic olefin and a highly substituted cyclohexane, that can be viewed as hybrids of the trans-fused avarol and cis-fused arenarol skeletons.
Phosphorus, Sulfur, and Silicon and the Related Elements, 2002
ABSTRACT Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the... more ABSTRACT Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the corresponding nucleoside aldehydes and tested for their ability to serve as substrates for nucleotide monophosphate kinase and for their toxicity to K562 leukemia cells.
Phosphorus, Sulfur, and Silicon and the Related Elements, 2014
ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and h... more ABSTRACT We have recently reported the synthesis of the first known phosphoantigen prodrug, and have demonstrated excellent gains in potency through delivery of the phosphoantigen to the intracellular domain of BTN3A1.
Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. Ho... more Phosphoantigen-sensitive Vγ9Vδ2 T cells are important responders to infections and malignancy. However, the mechanisms by which phosphoantigens stimulate Vγ9Vδ2 T cells are unclear. Here, we synthesized phosphoantigen prodrugs and used them to demonstrate that intracellular delivery of phosphoantigens is required for their activity. The pivaloyloxymethyl prodrug is the most potent phosphoantigen described to date, with stronger stimulation of Vγ9Vδ2 T cells from human peripheral blood and greater ability to induce lysis of Daudi lymphoma cells relative to the previously most potent compound, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). We demonstrate high binding affinity between phosphoantigens and the intracellular region of butyrophilin 3A1 (BTN3A1), localized to the PRY/SPRY (B30.2) domain, but also affecting the membrane proximal region. Our findings promote a phosphoantigen prodrug approach for cancer immunotherapy and unravel fundamental aspects of the mechanisms ...
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Papers by David Wiemer