15 research outputs found
Highly Regio- and Enantioselective Alkoxycarbonylative Amination of Terminal Allenes Catalyzed by a Spiroketal-Based Diphosphine/Pd(II) Complex
An enantioselective
alkoxycarbonylation–amination cascade
process of terminal allenes with CO, methanol, and arylamines has
been developed. It proceeds under mild conditions (room temperature,
ambient pressure CO) via oxidative PdÂ(II) catalysis using an aromatic
spiroketal-based diphosphine (SKP) as a chiral ligand and a CuÂ(II)
salt as an oxidant and affords a wide range of α-methylene-β-arylamino
acid esters (36 examples) in good yields with excellent enantioselectivity
(up to 96% ee) and high regioselectivity (branched/linear > 92:8).
Preliminary mechanistic studies suggested that the reaction is likely
to proceed through alkoxycarbonylpalladation of the allene followed
by an amination process. The synthetic utility of the protocol is
showcased in the asymmetric construction of a cycloheptene-fused chiral
β-lactam
Selective Palladium-Catalyzed Carbonylation of Alkynes: An Atom-Economic Synthesis of 1,4-Dicarboxylic Acid Diesters
A class
of novel diphosphine ligands bearing pyridine substituents
was designed and synthesized for the first time. The resulting palladium
complexes of <b>L1</b> allow for chemo- and regioselective dialkoxycarbonylation
of various aromatic and aliphatic alkynes affording a wide range of
1,4-dicarboxylic acid diesters in high yields and selectivities. Kinetic
studies suggest the generation of 1,4-dicarboxylic acid diesters via
cascade hydroesterification of the corresponding alkynes. Based on
these investigations, the chemo- and regioselectivities of alkyne
carbonylations can be controlled as shown by switching the ligand
from <b>L1</b> to <b>L3</b> or <b>L9</b> to give
α,β-unsaturated esters
Directly Grow Ultrasmall Co<sub>2</sub>P QDs on MoS<sub>2</sub> Nanosheets to Form Heterojunctions Greatly Boosting Electron Transfer toward Hydrogen Evolution
A green process to produce an efficient and inexpensive
electrocatalyst
toward hydrogen evolution reaction (HER) is of importance for hydrogen
energy. Here, an efficient HER electrocatalyst is made by electrochemically
depositing Co2P quantum dots (QDs) on MoS2-carbon
cloth (Co2P QDs/MoS2-CC). Due to the MoS2 porous structure, ∼3 nm Co2P QDs uniformly
deposit on MoS2. The produced unique 3D-structured Co2P QDs/MoS2-CC not only prevents an agglomeration
of the active material and improves the diffusion rate of H2 but also renders large accessible surface area and hierarchical
pores for high-density reaction sites and enhanced mass transport
rate. Experimental results and theoretical analysis of this unique
heterostructure indicate that the evolution process of hydrogen is
dominated by proton adsorption, and the introduction of sufficient
edge active sites can significantly promote the HER. As a consequence,
the hierarchical Co2P QDs/MoS2-CC electrocatalyst
affords an ultra-low overpotential (41 mV at a current density of
10 mA cm–2) that ranks the best among all reported
MoS2 HER catalysts and exhibits excellent durability in
1 M KOH solutions, thus holding great promise for the practical application
while shedding on fundamentals to nanoengineering an efficient electrocatalyst
Nanosized Aspirin-Arg-Gly-Asp-Val: Delivery of Aspirin to Thrombus by the Target Carrier Arg-Gly-Asp-Val Tetrapeptide
Resistance and nonresponse to aspirin dramatically decreases its therapeutic efficacy. To overcome this issue, a small-molecule thrombus-targeting drug delivery system, aspirin-Arg-Gly-Asp-Val (A-RGDV), is developed by covalently linking Arg-Gly-Asp-Val tetrapeptide with aspirin. The 2D ROESY NMR and ESI-MS spectra support a molecular model of an A-RGDV tetramer. Transmission electron microscopy images suggest that the tetramer spontaneously assembles to nanoparticles (ranging from 5 to 50 nm in diameter) in water. Scanning electron microscopy images and atomic force microscopy images indicate that the smaller nanoparticles of A-RGDV further assemble to bigger particles that are stable in rat blood. The delivery investigation implies that in rat blood A-RGDV is able to keep its molecular integrity, while in a thrombus it releases aspirin. The <i>in vitro</i> antiplatelet aggregation assay suggests that A-RGDV selectively inhibits arachidonic acid induced platelet aggregation. The mechanisms of action probably include releasing aspirin, modifying cyclic oxidase, and decreasing the expression of GPIIb/IIIa. The <i>in vivo</i> assay demonstrates that the effective antithrombotic dose of A-RGDV is 16700-fold lower than the nonresponsive dose of aspirin
7-Ethynylcoumarins: Selective Inhibitors of Human Cytochrome P450s 1A1 and 1A2
To discover new selective mechanism-based P450 inhibitors,
eight
7-ethynylcoumarin derivatives were prepared through a facile two-step
synthetic route. Cytochrome P450 activity assays indicated that introduction
of functional groups in the backbone of coumarin could enhance the
inhibition activities toward P450s 1A1 and 1A2, providing good selectivity
against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin
(7ETMC) showed IC<sub>50</sub> values of 0.46 μM and 0.50 μM
for P450s 1A1 and 1A2 in the first six minutes, respectively, and
did not show any inhibition activity for P450s 2A6 and 2B1 even at
the dose of 50 μM. All of the inhibitors except 7-ethynyl-3-methyl-4-phenylcoumarin
(7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2.
In order to explain this mechanistic difference in inhibitory activities,
X-ray crystallography data were used to study the difference in conformation
between 7E3M4PC and the other compounds studied. Docking simulations
indicated that the binding orientations and affinities resulted in
different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC
with its two-plane structure fits into the P450 1A2’s active
site cavity with an orientation leading to no reactive binding, causing
it to act as a competitive inhibitor
7-Ethynylcoumarins: Selective Inhibitors of Human Cytochrome P450s 1A1 and 1A2
To discover new selective mechanism-based P450 inhibitors,
eight
7-ethynylcoumarin derivatives were prepared through a facile two-step
synthetic route. Cytochrome P450 activity assays indicated that introduction
of functional groups in the backbone of coumarin could enhance the
inhibition activities toward P450s 1A1 and 1A2, providing good selectivity
against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin
(7ETMC) showed IC<sub>50</sub> values of 0.46 μM and 0.50 μM
for P450s 1A1 and 1A2 in the first six minutes, respectively, and
did not show any inhibition activity for P450s 2A6 and 2B1 even at
the dose of 50 μM. All of the inhibitors except 7-ethynyl-3-methyl-4-phenylcoumarin
(7E3M4PC) showed mechanism-based inhibition of P450s 1A1 and 1A2.
In order to explain this mechanistic difference in inhibitory activities,
X-ray crystallography data were used to study the difference in conformation
between 7E3M4PC and the other compounds studied. Docking simulations
indicated that the binding orientations and affinities resulted in
different behaviors of the inhibitors on P450 1A2. Specifically, 7E3M4PC
with its two-plane structure fits into the P450 1A2’s active
site cavity with an orientation leading to no reactive binding, causing
it to act as a competitive inhibitor
Poly-α,β-dl-Aspartyl‑l‑Cysteine: A Novel Nanomaterial Having a Porous Structure, Special Complexation Capability for Pb(II), and Selectivity of Removing Pb(II)
Poly-α,β-dl-aspartic acid is known
as a green chelant of various metal ions. To provide a novel nanochelant
for treating PbÂ(II) poisoning, poly-α,β-dl-aspartic
acid was modified with l-Cys to form poly-α,β-dl-aspartyl-l-cysteine (PDC; MW, 27273). dl-Asp was converted into polysuccinimide through a thermal polycondensation,
and the amidation of polysuccinimide with l-Cys provided
PDC. In water, PDC formed various porous nanospecies. In the mouse
lead intoxication model, both intraperitoneal and oral administration
of PDC (0.1, 1.0, and 10.0 nmol/kg) dose dependently removed PbÂ(II)
accumulated in the organ, bone, and blood. PDC did not remove the
essential metals including Cu<sup>2+</sup>, Fe<sup>2+</sup>, Mn<sup>2+</sup>, Zn<sup>2+</sup>, and Ca<sup>2+</sup> of the treated mice.
The porous feature and size of the pH- and concentration-dependent
nanospecies of PDC benefited the removal of PbÂ(II)
Synthesis and <i>In Vivo</i> Lead Detoxification Evaluation of Poly-α,β-dl-aspartyl-l-methionine
To increase the metal selectivity of polyaspartic acid,
a so-called
green chelant, poly-α,β-dl-aspartyl-l-methionine (PDM) was synthesized as a novel lead chelating agent.
The phosphoric acid (80%) catalyzed thermal poly condensation of dl-aspartic acid provided poly succinimide, which was amidated
with l-methionine to form PDM (MW: 29161). At the doses of
0.1, 1.0, and 10.0 nmol/kg, either by intraperitoneal injection (i.p.)
or oral administration, PDM removed Pb from the spleens, hearts, and
kidneys of mice, especially dose-dependently decreasing the accumulation
of Pb in the brains, livers, and femurs of the mice, and did not interfere
with the essential metals, including Cu, Fe, Mn, and Ca. Even at the
dose of 0.1 nmol/kg, the i.p. injection of PDM removed Pb from the
spleens, hearts, and kidneys of mice and increased the amount of urinary
volume and urinary Pb, and the amount of fecal matter and the amount
of fecal Pb, resulting in effective removal of Pb from the body of
mice given Pb by i.p. injection. Our findings revealed that in aqueous
solution PDM formed diverse nanospecies
Pyranoflavones: A Group of Small-Molecule Probes for Exploring the Active Site Cavities of Cytochrome P450 Enzymes 1A1, 1A2, and 1B1
Selective inhibition of P450 enzymes
is the key to block the conversion of environmental procarcinogens
to their carcinogenic metabolites in both animals and humans. To discover
highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1,
as well as to investigate active site cavities of these enzymes, 14
novel flavone derivatives were prepared as chemical probes. Fluorimetric
enzyme inhibition assays were used to determine the inhibitory activities
of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly
selective P450 1B1 inhibitor 5-hydroxy-4′-propargyloxyflavone
(5H4′FPE) was discovered. Some tested compounds also showed
selectivity between P450s 1A1 and 1A2. α-Naphthoflavone-like
and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2,
while β-naphthoflavone-like flavone derivatives showed selective
inhibition of P450 1A1. On the basis of structural analysis, the active
site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating
a planar long strip cavity and a planar triangular cavity, respectively
Potent Mechanism-Based Inactivation of Cytochrome P450 2B4 by 9‑Ethynylphenanthrene: Implications for Allosteric Modulation of Cytochrome P450 Catalysis
The mechanism-based inactivation of cytochrome P450 2B4
(CYP2B4)
by 9-ethynylphenanthrene (9EP) has been investigated. The partition
ratio and <i>k</i><sub>inact</sub> are 0.2 and 0.25 min<sup>–1</sup>, respectively. Intriguingly, the inactivation exhibits
sigmoidal kinetics with a Hill coefficient of 2.5 and an <i>S</i><sub>50</sub> of 4.5 μM indicative of homotropic cooperativity.
Enzyme inactivation led to an increase in mass of the apo-CYP2B4 by
218 Da as determined by electrospray ionization liquid chromatography
and mass spectrometry, consistent with covalent protein modification.
The modified CYP2B4 was purified to homogeneity and its structure
determined by X-ray crystallography. The structure showed that 9EP
is covalently attached to Oγ of Thr 302 via an ester bond, which
is consistent with the increased mass of the protein. The presence
of the bulky phenanthrenyl ring resulted in inward rotations of Phe
297 and Phe 206, leading to a compact active site. Thus, binding of
another molecule of 9EP in the active site is prohibited. However,
results from the quenching of 9EP fluorescence by unmodified or 9EP-modified
CYP2B4 revealed at least two binding sites with distinct affinities,
with the low-affinity site being the catalytic site and the high-affinity
site on the protein periphery. Computer-aided docking and molecular
dynamics simulations with one or two ligands bound revealed that the
high-affinity site is situated at the entrance of a substrate access
channel surrounded by the F′ helix, β1−β2
loop, and β4 loop and functions as an allosteric site to enhance
the efficiency of activation of the acetylenic group of 9EP and subsequent
covalent modification of Thr 302