N-(1-Acetyl-r-7,c-9-diphenyl-4,8-dithia-1,2-diaza­spiro­[5.4]dec-2-en-3-yl)acet­amide

In the title compound, C22H23N3O2S2, the five-membered ring is planar and the C5S ring adopts a chair conformation. The crystal packing is stabilized by inter­molecular N—H⋯O and C—H⋯O inter­actions, generating a chain and a centrosymmetric dimer, respectively

Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia–ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns

Revisiting the mechanism of coagulation factor XIII activation and regulation from a structure/functional perspective

The activation and regulation of coagulation Factor XIII (FXIII) protein has been the subject of active research for the past three decades. Although discrete evidence exists on various aspects of FXIII activation and regulation a combinatorial structure/functional view in this regard is lacking. In this study, we present results of a structure/function study of the functional chain of events for FXIII. Our study shows how subtle chronological submolecular changes within calcium binding sites can bring about the detailed transformation of the zymogenic FXIII to its activated form especially in the context of FXIIIA and FXIIIB subunit interactions. We demonstrate what aspects of FXIII are important for the stabilization (first calcium binding site) of its zymogenic form and the possible modes of deactivation (thrombin mediated secondary cleavage) of the activated form. Our study for the first time provides a structural outlook of the FXIIIA 2 B 2 heterotetramer assembly, its association and dissociation. The FXIIIB subunits regulatory role in the overall process has also been elaborated upon. In summary, this study provides detailed structural insight into the mechanisms of FXIII activation and regulation that can be used as a template for the development of future highly specific therapeutic inhibitors targeting FXIII in pathological conditions like thrombosis

Direct observation of α-oxo ketenes from the photolysis of α-diazo β-diketones

Monitoring by IR spectroscopy of the broad-band irradiation of the symmetrically substituted 2-diazocyclohexane-1,3-dione (11), 3-diazopentane-2,4-dione (19), and 4-diazo-2,2,6,6-tetramethylheptane-3,5-dione (24) in Ar matrices at 12 K showed the formation of 2-carbonylcyclopentanone (s-Z-12), acetyl(methyl)ketene (s-E-20), and tert-butyl(pivaloyl)ketene (s-E-25), respectively, in less than 10 min. On increasing the photolysis time to >3 h, the α-oxo ketenes 12, 20, and 25 decarbonylated to the corresponding oxocarbenes which underwent Wolff rearrangement to carbonylcyclobutane (15), dimethylketene (23), and di-tert-butylketene (28), respectively. The reaction of 2-carbonylcyclopentanone (12) with CH3OH was monitored by IR spectroscopy. Thus, it was found that the reaction started at ca. 100 K and was essentially complete at 140 K, involving the initial formation of the enol form (9) of methyl 2-oxocyclopentanecarboxylate

Ethynamine - Ketenimine - Acetonitrile - Rearrangements: A computational Study of Flash Vacuum Pyrolysis Processes

The rearrangements of ethynamine 3 (H-CºC-NH2) to ketenimine 4 (CH2=C=NH) and acetonitrile 5 (CH3CN) were investigated computationally up to the MP4(SDTQ)/6-31G*//MP2(FU)/6-31G* level. The calculated barrier for a concerted reaction 3 -> 4 is very high, 74 kcal/mol, the structure of the transition state very unusual, and this path is discredited. A lower barrier of about 60 kcal/mol via aminovinylidene 2 and imidoylcarbene 15 has been found. The calculated barrier for a concerted second step 4 -> 5 is 61 kcal/mol, and the transition state structure is again very unusual with a virtually linear CCN backbone, but this does not appear to correspond to physical reality. Instead, CASPT2 calculations predict reaction via vinylnitrene 9 and/or homolysis of 4 to the radical pair ·CH2CN + H· (11) with a barrier of 67-70 kcal/mol in agreement with experimental shock-tube data. Recombination (maybe via roaming) affords acetonitrile 5. There is strong experimental evidence for homolytic paths in pas-phase pyrolyses of ketenimines.</p

Ethynamine - Ketenimine - Acetonitrile - Rearrangements: A computational Study of Flash Vacuum Pyrolysis Processes

<p>The rearrangements of ethynamine <b>3</b> (H-CºC-NH₂) to ketenimine <b>4</b> (CH₂=C=NH) and acetonitrile <b>5</b> (CH₃CN) were investigated computationally up to the MP4(SDTQ)/6-31G*//MP2(FU)/6-31G* level. The calculated barrier for a concerted reaction <b>3</b> -> <b>4</b> is very high, 74 kcal/mol, the structure of the transition state very unusual, and this path is discredited. A lower barrier of about 60 kcal/mol via aminovinylidene <b>2</b> and imidoylcarbene <b>15</b> has been found. The calculated barrier for a concerted second step <b>4 </b>-><b> 5</b> is 61 kcal/mol, and the transition state structure is again very unusual with a virtually linear CCN backbone, but this does not appear to correspond to physical reality. Instead, CASPT2 calculations predict reaction via vinylnitrene <b>9</b> and/or homolysis of <b>4 </b>to the radical pair ·CH₂CN + H· (<b>11</b>) with a barrier of 67-70 kcal/mol in agreement with experimental shock-tube data. Recombination (maybe via roaming) affords acetonitrile <b>5</b>. There is strong experimental evidence for homolytic paths in pas-phase pyrolyses of ketenimines.</p