10 research outputs found
Efficient and Stereocontrolled Synthesis of 1,2,4-Trioxolanes Useful for Ferrous Iron-Dependent Drug Delivery
Ferrous iron-promoted reduction of
a hindered peroxide bond underlies
the antimalarial action of the 1,2,4-trioxane artemisinin and the
1,2,4-trioxolane arterolane. In appropriately designed systems, a
1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent
and parasite-selective drug delivery, both in vitro and in vivo. A
stereocontrolled, expeditious (three steps), and efficient (67–71%
overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite
3″ substitution pattern that enables ferrous iron-dependent
drug delivery is reported. The key synthetic step involves a diastereoselective
Griesbaum co-ozonolysis reaction to afford primarily products with
a <i>trans</i> relationship between the 3″ substituent
and the peroxide bridge, as confirmed by X-ray structural analysis
of a 3″-substituted 4-nitrobenzoate analogue
Effect of Basic Site Substituents on Concerted Proton–Electron Transfer in Hydrogen-Bonded Pyridyl–Phenols
Separated concerted proton–electron transfer (sCPET)
reactions
of two series of phenols with pendent substituted pyridyl moieties
are described. The pyridine is either attached directly to the phenol
(<b>HOAr-pyX</b>) or connected through a methylene linker (<b>HOArCH</b><sub><b>2</b></sub><b>pyX</b>) (X = 4-NO<sub>2</sub>, 5-CF<sub>3</sub>, 4-CH<sub>3</sub>, and 4-NMe<sub>2</sub>). Electron-donating and -withdrawing substituents have a substantial
effect on the chemical environment of the transferring proton, as
indicated by IR and <sup>1</sup>H NMR spectra, X-ray structures, and
computational studies. One-electron oxidation of the phenols occurs
concomitantly with proton transfer from the phenolic oxygen to the
pyridyl nitrogen. The oxidation potentials vary linearly with the
p<i>K</i><sub>a</sub> of the free pyridine (pyX), with slopes
slightly below the Nerstian value of 59 mV/p<i>K</i><sub>a</sub>. For the <b>HOArCH</b><sub><b>2</b></sub><b>pyX</b> series, the rate constants <i>k</i><sub>sCPET</sub> for oxidation by NAr<sub>3</sub><sup>•+</sup> or [Fe(diimine)<sub>3</sub>]<sup>3+</sup> vary primarily with the thermodynamic driving
force (Δ<i>G</i>°<sub>sCPET</sub>), whether Δ<i>G</i>° is changed by varying the potential of the oxidant
or the substituent on the pyridine, indicating a constant intrinsic
barrier λ. In contrast, the substituents in the <b>HOAr-pyX</b> series affect λ as well as Δ<i>G</i>°<sub>sCPET</sub>, and compounds with electron-withdrawing substituents
have significantly lower reactivity. The relationship between the
structural and spectroscopic properties of the phenols and their CPET
reactivity is discussed
Effect of Basic Site Substituents on Concerted Proton–Electron Transfer in Hydrogen-Bonded Pyridyl–Phenols
Separated concerted proton–electron transfer (sCPET)
reactions
of two series of phenols with pendent substituted pyridyl moieties
are described. The pyridine is either attached directly to the phenol
(<b>HOAr-pyX</b>) or connected through a methylene linker (<b>HOArCH</b><sub><b>2</b></sub><b>pyX</b>) (X = 4-NO<sub>2</sub>, 5-CF<sub>3</sub>, 4-CH<sub>3</sub>, and 4-NMe<sub>2</sub>). Electron-donating and -withdrawing substituents have a substantial
effect on the chemical environment of the transferring proton, as
indicated by IR and <sup>1</sup>H NMR spectra, X-ray structures, and
computational studies. One-electron oxidation of the phenols occurs
concomitantly with proton transfer from the phenolic oxygen to the
pyridyl nitrogen. The oxidation potentials vary linearly with the
p<i>K</i><sub>a</sub> of the free pyridine (pyX), with slopes
slightly below the Nerstian value of 59 mV/p<i>K</i><sub>a</sub>. For the <b>HOArCH</b><sub><b>2</b></sub><b>pyX</b> series, the rate constants <i>k</i><sub>sCPET</sub> for oxidation by NAr<sub>3</sub><sup>•+</sup> or [Fe(diimine)<sub>3</sub>]<sup>3+</sup> vary primarily with the thermodynamic driving
force (Δ<i>G</i>°<sub>sCPET</sub>), whether Δ<i>G</i>° is changed by varying the potential of the oxidant
or the substituent on the pyridine, indicating a constant intrinsic
barrier λ. In contrast, the substituents in the <b>HOAr-pyX</b> series affect λ as well as Δ<i>G</i>°<sub>sCPET</sub>, and compounds with electron-withdrawing substituents
have significantly lower reactivity. The relationship between the
structural and spectroscopic properties of the phenols and their CPET
reactivity is discussed
Napyradiomycin Derivatives, Produced by a Marine-Derived Actinomycete, Illustrate Cytotoxicity by Induction of Apoptosis
The microbial production, isolation,
and structure elucidation of four new napyradiomycin congeners (<b>1</b>–<b>4</b>) is reported. The structures of these
compounds, which are new additions to the marine-derived meroterpenoids,
were defined by comprehensive spectroscopic analysis and by X-ray
crystallography. Using fluorescence-activated cell sorting (FACS)
analysis, napyradiomycins <b>1</b>–<b>4</b> were
observed to induce apoptosis in the colon adenocarcinoma cell line
HCT-116, indicating the possibility of a specific biochemical target
for this class of cytotoxins
Cobalt 1,3-Diisopropyl-1<i>H</i>-imidazol-2-ylidene Complexes: Synthesis, Solid-State Structures, and Quantum Chemistry Calculations
The reaction of (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(PPh<sub>3</sub>)<sub>2</sub> (<b>1</b>) with 1,3-bis(isopropyl)imidazol-2-ylidene (Im<sup><i>i</i></sup>Pr<sub>2</sub>, <b>17</b>) leads to the formation of (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(PPh<sub>3</sub>)(Im<sup><i>i</i></sup>Pr<sub>2</sub>) (<b>5</b>) in 69% yield. N-Heterocyclic carbene <b>17</b> also undergoes reaction with (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(CO)<sub>2</sub> (<b>9</b>) to give (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(Im<sup><i>i</i></sup>Pr<sub>2</sub>)(CO) (<b>6</b>) in 30% yield. The barrier to rotation about the Co−C<sup>carbene</sup> bond in <b>6</b> has been determined by variable-temperature <sup>1</sup>H NMR spectroscopy (13.6 kcal/mol) and by computation (13.3 kcal/mol). Complex <b>5</b> undergoes reaction with PhSSPh to give the paramagnetic thiolato complex (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(Im<sup><i>i</i></sup>Pr<sub>2</sub>)(SPh) (<b>7</b>), which is oxidized to the metallosulfone complex (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(Im<sup><i>i</i></sup>Pr<sub>2</sub>)(SO<sub>2</sub>Ph) (<b>8</b>). The solid-state structures of <b>5</b>−<b>8</b> were determined by X-ray crystallography. The structural and dynamic properties of <b>6</b>, (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(ImMe<sub>2</sub>)(CO) (ImMe<sub>2</sub> = 1,3-dimethylimidazol-2-ylidene), and (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(ImAr<sub>2</sub>)(CO) (ImAr<sub>2</sub> = 1,3-dimesityl-2-ylidene) were examined by quantum chemistry calculations
Cobalt 1,3-Diisopropyl-1<i>H</i>-imidazol-2-ylidene Complexes: Synthesis, Solid-State Structures, and Quantum Chemistry Calculations
The reaction of (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(PPh<sub>3</sub>)<sub>2</sub> (<b>1</b>) with 1,3-bis(isopropyl)imidazol-2-ylidene (Im<sup><i>i</i></sup>Pr<sub>2</sub>, <b>17</b>) leads to the formation of (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(PPh<sub>3</sub>)(Im<sup><i>i</i></sup>Pr<sub>2</sub>) (<b>5</b>) in 69% yield. N-Heterocyclic carbene <b>17</b> also undergoes reaction with (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(CO)<sub>2</sub> (<b>9</b>) to give (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(Im<sup><i>i</i></sup>Pr<sub>2</sub>)(CO) (<b>6</b>) in 30% yield. The barrier to rotation about the Co−C<sup>carbene</sup> bond in <b>6</b> has been determined by variable-temperature <sup>1</sup>H NMR spectroscopy (13.6 kcal/mol) and by computation (13.3 kcal/mol). Complex <b>5</b> undergoes reaction with PhSSPh to give the paramagnetic thiolato complex (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(Im<sup><i>i</i></sup>Pr<sub>2</sub>)(SPh) (<b>7</b>), which is oxidized to the metallosulfone complex (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(Im<sup><i>i</i></sup>Pr<sub>2</sub>)(SO<sub>2</sub>Ph) (<b>8</b>). The solid-state structures of <b>5</b>−<b>8</b> were determined by X-ray crystallography. The structural and dynamic properties of <b>6</b>, (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(ImMe<sub>2</sub>)(CO) (ImMe<sub>2</sub> = 1,3-dimethylimidazol-2-ylidene), and (η<sup>5</sup>-C<sub>5</sub>H<sub>5</sub>)Co(ImAr<sub>2</sub>)(CO) (ImAr<sub>2</sub> = 1,3-dimesityl-2-ylidene) were examined by quantum chemistry calculations
Chiral Amide Directed Assembly of a Diastereo- and Enantiopure Supramolecular Host and its Application to Enantioselective Catalysis of Neutral Substrates
The
synthesis of a novel supramolecular tetrahedral assembly of K<sub>12</sub>Ga<sub>4</sub>L<sub>6</sub> stoichiometry is reported. The
newly designed chiral ligand exhibits high diastereoselective control
during cluster formation, leading exclusively to a single diastereomer
of the desired host. This new assembly also exhibits high stability
toward oxidation or a low pH environment and is a more robust and
efficient catalyst for asymmetric organic transformations of neutral
substrates
Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy
Multicomponent solids such as
cocrystals have emerged as a way
to control and engineer the stability, solubility, and manufacturability
of solid active pharmaceutical ingredients (APIs). Cocrystals are
typically formed by solution- or solid-phase reactions of APIs with
suitable cocrystal coformers, which are often weak acids. One key
structural question about a given multicomponent solid is whether
it should be classified as a salt, where the basic API is protonated
by the acid, or as a cocrystal, where the API and coformer remain
neutral and engage in hydrogen bonding interactions. It has previously
been demonstrated that solid-state NMR spectroscopy is a powerful
probe of structure in cocrystals and salts of APIs; however, the poor
sensitivity of solid-state NMR spectroscopy usually restricts the
types of experiments that can be performed. Here, relayed dynamic
nuclear polarization (DNP) was applied to reduce solid-state NMR experiment
times by 1–2 orders of magnitude for salts and cocrystals of
a complex API. The large sensitivity gains from DNP facilitates rapid
acquisition of natural isotopic abundance <sup>13</sup>C and <sup>15</sup>N solid-state NMR spectra. Critically, DNP enables double
resonance <sup>1</sup>H–<sup>15</sup>N solid-state NMR experiments
such as 2D <sup>1</sup>H–<sup>15</sup>N HETCOR, <sup>1</sup>H–<sup>15</sup>N CP-build up, <sup>15</sup>N{<sup>1</sup>H} <i>J</i>-resolved/attached proton tests, <sup>1</sup>H–<sup>15</sup>N DIPSHIFT, and <sup>1</sup>H–<sup>15</sup>N PRESTO.
The latter two experiments allow <sup>1</sup>H–<sup>15</sup>N dipolar coupling constants and H–N bond lengths to be accurately
measured, providing an unambiguous assignment of nitrogen protonation
state and definitive classification of the multicomponent solids as
cocrystals or salts. These types of measurements should also be extremely
useful in the context of polymorph discrimination, NMR crystallography
structure determination, and for probing hydrogen bonding in a variety
of organic materials
Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors
Structure-based
methods were used to design a potent and highly
selective group II p21-activated kinase (PAK) inhibitor with a novel
binding mode, compound <b>17</b>. Hydrophobic interactions within
a lipophilic pocket past the methionine gatekeeper of group II PAKs
approached by these type I 1/2 binders were found to be important
for improving potency. A structure-based hypothesis and strategy for
achieving selectivity over group I PAKs, and the broad kinome, based
on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent
decrease in tumor cell migration and invasion in two triple-negative
breast cancer cell lines was observed with compound <b>17</b>
Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice
A series
of trisubstituted hydroxylactams was identified as potent
enzymatic and cellular inhibitors of human lactate dehydrogenase A.
Utilizing structure-based design and physical property optimization,
multiple inhibitors were discovered with <10 μM lactate IC<sub>50</sub> in a MiaPaca2 cell line. Optimization of the series led
to <b>29</b>, a potent cell active molecule (MiaPaca2 IC<sub>50</sub> = 0.67 μM) that also possessed good exposure when
dosed orally to mice