Edward R. Biehl

Transmission of substituent effects in anilinetricarbonylchromium compounds

The acidities of several substituted phenoltricarbonylchromium compounds have been determined in 50% ethanol. A plot of pKa values versus Hammett substituent constants indicates that no distortion of substituent effects occurs upon complexation of an aromatic system to the tricarbonylchromium moiety.

Synthesis of Optically Pure 2-Azido-1-arylethanols with Isolated Enzymes and Conversion to Triazole-Containing β-Blocker Analogues Employing Click Chemistry

Both antipodes of 2-azido-1-arylethanols were synthesized with excellent optical purity via enzymatic reduction of the corresponding alpha-azidoacetophenone derivatives catalyzed by a recombinant carbonyl reductase from Candida magnoliae ( CMCR) or an alcohol dehydrogenase from Saccharomyces cerevisiae ( Ymr226c). This provides an effective route to this class of important compounds in optically pure form. ( S)-2-Azido-1-( p-chlorophenyl)ethanols reacted with alkynes employing click chemistry to afford high yields of optically pure triazole-containing beta-adrenergic receptor blocker analogues with potential biological activity.

Reaction of pentadienyliron tricarbonyl cations with hydride donors

Abstract A series of pentadienyliron tricarbonyl cations has been prepared and reacted with the hydride ion donors sodium borohydride, sodium cyanoborohydride, and lithium triethylborohydride in order to determine steric and electronic effects in these reduction reactions. Sodium cyanoborohydride yields products of retained configuration whereas lithium triethylborohydride yields dieneiron tricarbonyl compounds of inverted configuration. Kinetic and thermodynamic considerations are used to account for these results.

The crystal structure of palmitoyl protein thioesterase-2 (PPT2) reveals the basis for divergent substrate specificities of the two lysosomal thioesterases, PPT1 and PPT2.

Mutations in palmitoyl protein thioesterase-1 (PPT1) have been found to cause the infantile form of neuronal ceroid lipofuscinosis, which is a lysosomal storage disorder characterized by impaired degradation of fatty acid-modified proteins with accumulation of amorphous granular deposits in cortical neurons, leading to mental retardation and death. Palmitoyl protein thioesterase-2 (PPT2) is a second lysosomal hydrolase that shares a 26% identity with PPT1. A previous study had suggested that palmitoyl-CoA was the preferred substrate of PPT2. Furthermore, PPT2 did not hydrolyze palmitate from the several S-palmitoylated protein substrates. Interestingly, PPT2 deficiency in a recent transgenic mouse model is associated with a form of neuronal ceroid lipofuscinosis, suggesting that PPT1 and -2 perform non-redundant roles in lysosomal thioester catabolism. In the current paper, we present the crystal structure of PPT2 at a resolution of 2.7 Å. Comparisons of the structures of PPT1 and -2 show very similar architectural features; however, conformational differences in helix α4 lead to a solvent-exposed lipid-binding groove in PPT1. The limited space between two parallel loops (β3-αA and β8-αF) located immediately above the lipid-binding groove in PPT2 restricts the binding of fatty acids with bulky head groups, and this binding groove is significantly larger in PPT1. This structural difference accounts for the ability of PPT2 to hydrolyze an unbranched structure such as palmitoyl-CoA but not palmitoylcysteine or palmitoylated proteins. Furthermore, differences in fatty acid chain length specificity of PPT1 and -2, also reported here, are explained by the structure and may provide a biochemical basis for their non-redundant roles.

Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration.

Neurodegenerative diseases such as Alzheimers disease, Parkinsons disease, and Huntingtons disease and conditions such as ischemic stroke affect millions of individuals annually and exert an enormous financial burden on society. A hallmark of these conditions is the abnormal loss of neurons. Currently, there are no effective strategies to prevent neuronal death in these pathologies. We report that several 2‐arylidine and 2‐hetarylidin derivatives of the 1,4‐benzoxazines class of compounds are highly protective in tissue culture models of neurodegeneration. Results obtained using pharmcalogical inhibitors indicate that neuroprotection by these compounds does not involve the Raf–MEK–ERK or PI‐3 kinase–Akt signaling pathways nor other survival‐promoting molecules such as protein kinase A (PKA), calcium calmodulin kinase A (CaMK), and histone deacetylases (HDACs). We tested one of these compounds, (Z)‐6‐amino‐2‐(3′,5′‐dibromo‐4′‐hydroxybenzylidene)‐2H‐benzo[b][1,4]oxazin‐3(4H)‐one, designated as HSB‐13, in the 3‐nitropropionic acid (3‐NP)‐induced mouse model of Huntingtons disease. HSB‐13 reduced striatal degeneration and improved behavioral performance in mice administered with 3‐NP. Furthermore, HSB‐13 was protective in a Drosophila model of amyloid precursor protein (APP) toxicity. To understand how HSB‐13 and other 1,4‐benzoxazines protect neurons, we performed kinase profiling analyses. These analyses showed that HSB‐13 inhibits GSK3, p38 MAPK, and cyclin‐dependent kinases (CDKs). In comparison, another compound, called ASK‐2a, that protects cerebellar granule neurons against low‐potassium‐induced death inhibits GSK3 and p38 MAPK but not CDKs. Despite its structural similarity to HSB‐13, however, ASK‐2a is incapable of protecting cortical neurons and HT22 cells against homocysteic acid (HCA)‐induced or Aβ toxicity, suggesting that protection against HCA and Aβ depends on CDK inhibition. Compounds described in this study represent a novel therapeutic tool in the treatment of neurodegenerative diseases.

A Convenient Synthesis of Azaanthraquinones via Polar Addition to Hetaryne Intermediates. Use of Carbaninons Derived from 3-Cyano-1(3H)-isobenzofuranones

A convenient synthesis of 2-azaanthraquinones using the reaction of carbanions derived from 3-cyano-1(3H)-isobenzofuranones which serve as 1,4-dipole equivalents and hetaryne intermediates generated from bromopyridines and lithium diisopropylamide is reported

Synthesis and Structure-Activity Relationship Studies of 3-Substituted Indolin-2-ones as Effective Neuroprotective Agents

Neurodegenerative diseases are a major health problem particularly among the elderly. Drugs to prevent or slow down the death of neurons are urgently needed but are currently unavailable. We previously reported that the c-Raf inhibitor, GW5074 {5-iodo-3-[(3′,5′-dibromo-4′-hydroxyphenyl) methylene]-2-indolinone}, is protective in tissue culture and in vivo paradigms of neurodegeneration. However, at doses slightly higher than those at which it is protective, GW5074 displays toxicity when tested in neuronal cultures. We report herein the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of novel 3-substituted indolin-2-one compounds that are highly neuroprotective but lack the toxicity of GW5074. Of the 45 analogs tested in this study, compounds 7, 37, 39, and 45 were found to be the most potent neuroprotective and thus represent promising lead compounds for preclinical development for the treatment of neurodegenerative disorders.

Reactions of unsymmetrically substituted pentadienyliron tricarbonyl cations with water

Abstract The reactions of unsymmetrically-substituted pentadienyliron tricarbonyl cations with water have been studied in order to learn more about the relative importance of steric and electronic factors in determining the position of nucleophilic attack.

An Efficient Synthesis of Benzene Fused Six-, Seven- and Eight-membered Rings Containing Nitrogen and Sulfur by Benzyne Ring Closure Reaction

3,4-Dihydro-2-H-benzo[1,4]thiazines (3a-c), 2,3,4,5-tetrahydro[b]-[1,4]thiazapines (3d-f) and 2,3,4,5-tetrahydro-2H-benzo[b][1,4]thiazocines (3g-i) were prepared by the cyclization of the respective 2-bromophenylsulfanyl derivatives of ethylamine (la-c), propylamine (2d-f) and butylamine (2g-i).

Preparation of Benzothiopyrano[2,3-b]indoles by the Reaction of 1,3-Dihydroindole-2-thiones with Certain Dienophiles

Benzothiopyrano[2,3-b]indoles were prepared by the cyclization of 1,3-dihydroindole-2-thiones with various dienophiles. The 1,3-dihydroindole-2-thiones were readily synthesized by the reaction of oxindole with P 2 S 5 followed by a piperidine-mediated condensation of the resulting thioindole with a suitable aromatic aldehyde.