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>_<b>2</b><b>pyX</b>) (X = 4-NO₂, 5-CF₃, 4-CH₃, and 4-NMe₂). Electron-donating and -withdrawing substituents have a substantial effect on the chemical environment of the transferring proton, as indicated by IR and ¹H 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>_a of the free pyridine (pyX), with slopes slightly below the Nerstian value of 59 mV/p<i>K</i>_a. For the <b>HOArCH</b>_<b>2</b><b>pyX</b> series, the rate constants <i>k</i>_sCPET for oxidation by NAr₃^•+ or [Fe­(diimine)₃]³⁺ vary primarily with the thermodynamic driving force (Δ<i>G</i>°_sCPET), 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>°_sCPET, 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>_<b>2</b><b>pyX</b>) (X = 4-NO₂, 5-CF₃, 4-CH₃, and 4-NMe₂). Electron-donating and -withdrawing substituents have a substantial effect on the chemical environment of the transferring proton, as indicated by IR and ¹H 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>_a of the free pyridine (pyX), with slopes slightly below the Nerstian value of 59 mV/p<i>K</i>_a. For the <b>HOArCH</b>_<b>2</b><b>pyX</b> series, the rate constants <i>k</i>_sCPET for oxidation by NAr₃^•+ or [Fe­(diimine)₃]³⁺ vary primarily with the thermodynamic driving force (Δ<i>G</i>°_sCPET), 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>°_sCPET, 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 (η⁵-C₅H₅)Co(PPh₃)₂ (<b>1</b>) with 1,3-bis(isopropyl)imidazol-2-ylidene (Im^<i>i</i>Pr₂, <b>17</b>) leads to the formation of (η⁵-C₅H₅)Co(PPh₃)(Im^<i>i</i>Pr₂) (<b>5</b>) in 69% yield. N-Heterocyclic carbene <b>17</b> also undergoes reaction with (η⁵-C₅H₅)Co(CO)₂ (<b>9</b>) to give (η⁵-C₅H₅)Co(Im^<i>i</i>Pr₂)(CO) (<b>6</b>) in 30% yield. The barrier to rotation about the Co−C^carbene bond in <b>6</b> has been determined by variable-temperature ¹H 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 (η⁵-C₅H₅)Co(Im^<i>i</i>Pr₂)(SPh) (<b>7</b>), which is oxidized to the metallosulfone complex (η⁵-C₅H₅)Co(Im^<i>i</i>Pr₂)(SO₂Ph) (<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>, (η⁵-C₅H₅)Co(ImMe₂)(CO) (ImMe₂ = 1,3-dimethylimidazol-2-ylidene), and (η⁵-C₅H₅)Co(ImAr₂)(CO) (ImAr₂ = 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 (η⁵-C₅H₅)Co(PPh₃)₂ (<b>1</b>) with 1,3-bis(isopropyl)imidazol-2-ylidene (Im^<i>i</i>Pr₂, <b>17</b>) leads to the formation of (η⁵-C₅H₅)Co(PPh₃)(Im^<i>i</i>Pr₂) (<b>5</b>) in 69% yield. N-Heterocyclic carbene <b>17</b> also undergoes reaction with (η⁵-C₅H₅)Co(CO)₂ (<b>9</b>) to give (η⁵-C₅H₅)Co(Im^<i>i</i>Pr₂)(CO) (<b>6</b>) in 30% yield. The barrier to rotation about the Co−C^carbene bond in <b>6</b> has been determined by variable-temperature ¹H 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 (η⁵-C₅H₅)Co(Im^<i>i</i>Pr₂)(SPh) (<b>7</b>), which is oxidized to the metallosulfone complex (η⁵-C₅H₅)Co(Im^<i>i</i>Pr₂)(SO₂Ph) (<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>, (η⁵-C₅H₅)Co(ImMe₂)(CO) (ImMe₂ = 1,3-dimethylimidazol-2-ylidene), and (η⁵-C₅H₅)Co(ImAr₂)(CO) (ImAr₂ = 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 K₁₂Ga₄L₆ 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 ¹³C and ¹⁵N solid-state NMR spectra. Critically, DNP enables double resonance ¹H–¹⁵N solid-state NMR experiments such as 2D ¹H–¹⁵N HETCOR, ¹H–¹⁵N CP-build up, ¹⁵N­{¹H} <i>J</i>-resolved/attached proton tests, ¹H–¹⁵N DIPSHIFT, and ¹H–¹⁵N PRESTO. The latter two experiments allow ¹H–¹⁵N 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 IC₅₀ in a MiaPaca2 cell line. Optimization of the series led to <b>29</b>, a potent cell active molecule (MiaPaca2 IC₅₀ = 0.67 μM) that also possessed good exposure when dosed orally to mice