Biocatalytic N-Alkylation of Amines Using Either Primary Alcohols or Carboxylic Acids via Reductive Aminase Cascades.

The alkylation of amines with either alcohols or carboxylic acids represents a mild and safe alternative to the use of genotoxic alkyl halides and sulfonate esters. Here we report two complementary one-pot systems in which the reductive aminase (RedAm) from Aspergillus oryzae is combined with either (i) a 1° alcohol/alcohol oxidase (AO) or (ii) carboxylic acid/carboxylic acid reductase (CAR) to affect N-alkylation reactions. The application of both approaches has been exemplified with respect to substrate scope and also preparative scale synthesis. These new biocatalytic methods address issues facing alternative traditional synthetic protocols such as harsh conditions, overalkylation and complicated workup procedures.

The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one).

ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.

Evaluation of fluoropyruvate as nucleophile in reactions catalysed by N-acetyl neuraminic acid lyase variants: scope, limitations and stereoselectivity.

The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90 : 10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30 : 70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied. Using fluoropyruvate and (2R,3S)- or (2S,3R)-2,3-dihydroxy-4-oxo-N,N-dipropylbutanamide as substrates, it was possible to obtain three of the four possible diastereomeric products; for each product, the ratio of anomeric and pyranose/furanose forms was determined. The crystal structure of S. aureus NAL in complex with fluoropyruvate was determined, assisting rationalisation of the stereochemical outcome of C-C bond formation.

An (R)-Imine Reductase Biocatalyst for the Asymmetric Reduction of Cyclic Imines.

Although the range of biocatalysts available for the synthesis of enantiomerically pure chiral amines continues to expand, few existing methods provide access to secondary amines. To address this shortcoming, we have over-expressed the gene for an (R)-imine reductase [(R)-IRED] from Streptomyces sp. GF3587 in Escherichia coli to create a recombinant whole-cell biocatalyst for the asymmetric reduction of prochiral imines. The (R)-IRED was screened against a panel of cyclic imines and two iminium ions and was shown to possess high catalytic activity and enantioselectivity. Preparative-scale synthesis of the alkaloid (R)-coniine (90 % yield; 99 % ee) from the imine precursor was performed on a gram-scale. A homology model of the enzyme active site, based on the structure of a closely related (R)-IRED from Streptomyces kanamyceticus, was constructed and used to identify potential amino acids as targets for mutagenesis.

Twenty-one bust: a case of chemical transformation of an ingested foreign body.

The majority of ingested foreign bodies pass of their own accord without causing any adverse impact on the patient, while others present a greater management dilemma. We present a case of a 36-year-old man admitted to the hospital with a 10-day history of colicky abdominal pain following voluntary ingestion of multiple pairs of vinyl gloves. The plain-film abdominal X-ray confirmed small bowel obstruction and gastric bezoar. After failed conservative management he opted for endoscopic retrieval. Following exposure to stomach acid the gloves had lost their structural integrity becoming hard, sharp and brittle. As a result endoscopic removal was abandoned due to the risk of traumatic injury to the oesophagus. A midline laparotomy was performed and the gloves were retrieved via enterotomy. While many foreign bodies are suitable for endoscopic extraction this case demonstrates that the retrieval of vinyl gloves is unlikely to be successful due to significant chemical change.

Radiological diagnosis of a small bowel perforation secondary to toothpick ingestion.

A 77-year-old edentulous man presented to the accident and emergency department with a sudden onset of sharp right-sided abdominal pain. The patient reported a change in his bowel habit with constipation over a 6 month period but did not report any significant choking event or ingestion of a foreign body in the preceding months. On examination the patient was maximally tender with guarding over McBurneys point. CT scan showed an abnormal segment of distal ileum with a 3 cm high attenuation focus which had penetrated the bowel wall. At laparotomy the patient was found to have a perforation of his distal ileum caused by an ingested toothpick. Patients wearing dental plates or dentures are at higher risk of toothpick ingestion due to impaired palatal sensation. CT scanning, in the appropriate setting, may aid diagnosis and lower operator risk of sharp related injury at the time of operation.

Double arylation of allyl alcohol via a one-pot Heck arylation-isomerization-acylation cascade.

A one-pot, two-step catalytic protocol has been developed. A regioselective Heck coupling between aryl bromides and allyl alcohol leads to the generation of arylated allyl alcohols that in situ isomerize to give aldehydes, which then undergo an acylation reaction with a second aryl bromide. A variety of aryl bromides can be employed in both the initial Heck reaction and the acylation, providing easy access to a wide variety of substituted dihydrochalcones.

Bifunctional catalysis: direct reductive amination of aliphatic ketones with an iridium-phosphate catalyst.

Chiral amines are one of the ubiquitous functional groups in fine chemical, pharmaceutical and agrochemical products, and the most convenient, economical, and eco-benign synthetic pathway to these amines is direct asymmetric reductive amination (DARA) of prochiral ketones. This paper shows that a wide range of aliphatic ketones can be directly aminated under hydrogenation conditions, affording chiral amines with good to excellent yields and with enantioselectivities up to 96% ee. The catalysis is effected by the cooperative action of a cationic Cp*Ir(III) complex and its phosphate counteranion.

Abdominal abscess due to retained gallstones 5 years after laparoscopic cholecystectomy.

A 76-year-old female patient with diabetes presented with pyrexia and a recurrent painful right sided loin swelling. One year previously she had undergone radiological drainage of a large right sided loin abscess. At index presentation she was investigated both radiologically and endoscopically and a source for the abscess was not found. On this presentation, a computed tomography scan confirmed a large retroperitoneal abscess pointing through the lateral abdominal wall musculature. Surgical drainage was undertaken whereby the abscess was drained and several large gallstones extruded through the incision. The patient subsequently recuperated and the wound has healed successfully by second intention. Five years previously the patient had undergone an "uncomplicated" laparoscopic cholecystectomy. This case highlights the catastrophic late effects of dropped gallstones during laparoscopic cholecystectomy.

Glycosylated foldamers to probe the carbohydrate-carbohydrate interaction.

The synthesis of a triglycosylated helical foldamer based on a combination of cyclopentyl- and pyrrolidinyl-based amino acids is described. This structure is stable in water, maintaining as it does a series of carbohydrate units in proximity to one another, and represents the basis of a new approach to the study of carbohydrate-carbohydrate interactions.

Pseudocyst formation in gastric ectopic pancreas.

CONTEXT: It is rare for ectopic pancreatic tissue to cause symptoms or require treatment, however diseases of normal pancreas may also occur in ectopic pancreas tissue. CASE REPORT: This report describes the clinical, endoscopic, radiologic and histologic features of a pseudocyst occurring in gastric ectopic pancreas in a 19-year-old man. The difficulty and implications of making an accurate pre-operative diagnosis are highlighted. CONCLUSION: Ectopic pancreatic tissue, although rare, should be considered in the differential diagnosis of a submucosal gastric mass.