Oxidative Ring Expansion of Spirocyclic Oxindole Derivatives

Oxidation of the spirocyclic oxindole derivative, isamic acid <b>1</b>, led to decarboxylation and ring expansion to quinazolino­[4,5-<i>b</i>]­quinazoline-6,8-dione <b>7</b> rather than, as previously believed, its isomer <b>6</b>. The structure of <b>7</b> was confirmed by X-ray crystallography. Condensation of isatin (indole-2,3-dione) and 2-aminobenzamide led to the spirocyclic molecule, spiro­[3<i>H</i>-indole-3,2′(1<i>H</i>)­quinazoline]-2,4′(1<i>H</i>,3<i>H</i>)­dione <b>8</b>, which was also identified as an intermediate in the oxidation of isamic acid. Mild hydrolysis of <b>7</b> gave the 10-membered molecule <b>22</b>. Isamic acid could easily be converted to <i>N</i>-nitrosoisamic acid, which when heated in ethanol underwent a ring expansion to a hydroximino derivative, <b>38</b>, of compound <b>6</b>. The structure of <b>38</b> was confirmed by X-ray crystallography

Oxidative Ring Expansion of Spirocyclic Oxindole Derivatives

Oxidation of the spirocyclic oxindole derivative, isamic acid <b>1</b>, led to decarboxylation and ring expansion to quinazolino­[4,5-<i>b</i>]­quinazoline-6,8-dione <b>7</b> rather than, as previously believed, its isomer <b>6</b>. The structure of <b>7</b> was confirmed by X-ray crystallography. Condensation of isatin (indole-2,3-dione) and 2-aminobenzamide led to the spirocyclic molecule, spiro­[3<i>H</i>-indole-3,2′(1<i>H</i>)­quinazoline]-2,4′(1<i>H</i>,3<i>H</i>)­dione <b>8</b>, which was also identified as an intermediate in the oxidation of isamic acid. Mild hydrolysis of <b>7</b> gave the 10-membered molecule <b>22</b>. Isamic acid could easily be converted to <i>N</i>-nitrosoisamic acid, which when heated in ethanol underwent a ring expansion to a hydroximino derivative, <b>38</b>, of compound <b>6</b>. The structure of <b>38</b> was confirmed by X-ray crystallography

Tuning of Molecular Water Organization in Water-in-Salt Electrolytes by Addition of Chaotropic Ionic Liquids

Water-in-salt electrolytes (WISEs) have expanded the useful electrochemical stability of water, making the development of functional aqueous lithium-ion batteries more accessible. The implementation of additives in the formulation of WISEs can further improve the electrochemical stability of water and avoid potential lithium-ion salt solubility issues. Here, we have used Gemini-type ionic liquids to suppress water activity by designing the structure of ionic-liquid cations. The different water-organizing effects of ionic-liquid cations have been investigated and correlated to battery performance in LTO/LMO full cells. The champion device, containing the most chaotropic ionic liquid, retained at least 99% of its Coulombic efficiency after 500 charging cycles, associated with a final specific discharge capacity of 85 mA h·g–1. These results indicated that water-rich Li+ solvation shells significantly contribute to the excellent device performance and long-term stability of the LTO/LMO-based full battery cells. This work shows that the fine-tuning of the Li+ solvation shell and water structure by the addition of chaotropic cations represents a promising strategy for generating more stable and effective lithium-ion-containing rechargeable aqueous batteries

<i>De Novo</i> Determination of the Crystal Structure of a Large Drug Molecule by Crystal Structure Prediction-Based Powder NMR Crystallography

The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]­benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state ¹H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far

Synthesis and Functionalization of Cyclic Sulfonimidamides: A Novel Chiral Heterocyclic Carboxylic Acid Bioisostere

An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar heterocyclic carboxylic acid bioisosteres is described. The cyclic sulfonimidamide ring system could be prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester protected amino acids. By varying the amino acid, a range of different C-3 substituted sulfonimidamides could be prepared. The compounds could be further derivatized in the aryl ring using standard cross-coupling reactions to yield highly substituted cyclic sulfonimidamides in excellent yields. The physicochemical properties of the final compounds were examined and compared to those of the corresponding carboxylic acid and tetrazole derivatives. The unique nonplanar shape in combination with the relatively strong acidity (p<i>K</i>_a 5–6) and the ease of modifying the chemical structure to fine-tune the physicochemical properties suggest that this heterocycle can be a valuable addition to the range of available carboxylic acid isosteres

<i>De Novo</i> Determination of the Crystal Structure of a Large Drug Molecule by Crystal Structure Prediction-Based Powder NMR Crystallography

The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-<i>tert</i>-butyl-pyrazol-1-yl]­benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state ¹H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far

The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features

Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (<b>1</b>) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound <b>1</b> is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of <b>1</b> and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma

The Oncolytic Efficacy and in Vivo Pharmacokinetics of [2-(4-Chlorophenyl)quinolin-4-yl](piperidine-2-yl)methanol (Vacquinol-1) Are Governed by Distinct Stereochemical Features

Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (<b>1</b>) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound <b>1</b> is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of <b>1</b> and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma

Substituted 7‑Amino-5-thio-thiazolo[4,5‑<i>d</i>]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX₃CR1)

We have developed two parallel series, A and B, of CX₃CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo­[4,5-<i>d</i>]­pyrimidine core structure, we were able to achieve compounds with high selectivity for CX₃CR1 over the closely related CXCR2 receptor. The structure–activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds <b>18a</b> and <b>24h</b>. We show the preparation of the first potent and selective orally available CX₃CR1 antagonists

Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists

Agonism of GPR119 is viewed as a potential therapeutic approach for the treatment of type II diabetes and other elements of metabolic syndrome. During progression of a previously disclosed candidate <b>1</b> through mice toxicity studies, we observed tonic–clonic convulsions in several mice at high doses. An in vitro hippocampal brain slice assay was used to assess the seizure liability of subsequent compounds, leading to the identification of an aryl sulfone as a replacement for the 3-cyano pyridyl group. Subsequent optimization to improve the overall profile, specifically with regard to hERG activity, led to alkyl sulfone <b>16</b>. This compound did not cause tonic–clonic convulsions in mice, had a good pharmacokinetic profile, and displayed in vivo efficacy in murine models. Importantly, it was shown to be effective in wild-type (WT) but not GPR119 knockout (KO) animals, consistent with the pharmacology observed being due to agonism of GPR119