Alcohol Analogues Research Articles

A Macrocyclic Calpain Inhibitor Slows the Development of Inherited Cortical Cataracts in a Sheep Model

We used sheep with an autosomal dominant gene for cortical cataract as an animal model to evaluate novel macrocyclic calpain inhibitors with potential for the medical treatment of human cataract. The macrocyclic aldehyde, CAT811, identified previously as a calpain inhibitor that prevents calcium-induced opacification in cultured sheep lenses, was tested for its ability to protect cytoskeletal proteins from calpain proteolysis. CAT811 and its alcohol analogue, CAT505, were formulated separately into ointments, and each was applied twice daily to the right eye of sheep with early cataracts for five months. Progress of cataracts in the sheep was determined by ophthalmologic examination and comparison with a matched sample of sheep treated similarly with ointment that did not contain the active ingredient. The novel macrocyclic aldehyde, CAT811, was able to inhibit calpain proteolysis of lens cytoskeletal proteins at micromolar concentrations. When applied topically to the eyes of sheep, CAT811 was able to slow cataract development by 27% in the initial three months of treatment (P < 0.05). Its alcohol analogue, CAT505, was not able to slow cataractogenesis significantly. The inherited sheep cataract provides a reproducible model of cortical cataract over a time scale of several months. The data reported here, using this model, demonstrated the potential of the macrocyclic calpain inhibitor, CAT811, to act as a therapeutic for treatment of cortical cataract.

Tryptanthrin derivatives as Toxoplasma gondii inhibitors—structure–activity-relationship of the 6-position

A panel of derivatives of the natural product tryptanthrin was synthesized and screened for its in vitro activity against the intracellular parasite Toxoplasma gondii. We concentrated on the modification of the 6-keto group of tryptanthrin and prepared a series of oximes, hydrazones and alcohols based on tryptanthrin. We evaluated parasite growth inhibition and host cell cytotoxicity. Our results indicate that in particular alcohol analogs are promising candidates for further investigation.

Efficient Synthesis of a New Series of Piperidine Ring–Modified Alcohol and Methyl Ether Analogs of (±)-threo-Methyl Phenyl(piperidin-2-yl)acetate

A series of novel piperidine ring–modified alcohol and methyl ether analogs of (±)-threo-methyl phenyl(piperidin-2-yl)acetate was synthesized. This series of methyl phenyl(piperidin-2-yl)acetate analogs was developed by piperidine ring alkylation and/or acylation followed by lithium aluminum hydride reduction to give alcohol derivatives. Methylation of the alcohol analogs by extension of standard literature procedures gave the corresponding methyl ether derivatives. The chemical structure of these compounds was established based on mass and 1H NMR spectral data and CHN elemental analysis data. Several significant modifications to the literature methodologies made the reaction more efficient, and good yields were generally obtained.

Abietane diterpenoids from some salvia species: Chemical transformations and antiproliferative activity

In this research the major secondary metabolites isolated from these species and their biological studies against five human cancer cell lines are described. A cold acetone extract of the aerial parts of S. pachyphylla was chromatographed on silica gel to give nine known natural products and the new diterpene identified on the basis of spectroscopic data analysis. From the aerial parts of S. clevelandii, seven known diterpenes were obtained and identified by comparison with the spectroscopic data found in the bibliography. The antiproliferative activity of the isolated metabolites was evaluated in vitro against A2780 ovarian cancer, SW1573 non-small-cell lung cancer, WiDr colon cancer, T-47D breast cancer, and HBL-100 breast cancer cells. Finally a series of β-amino alcohol analogs of sugiol were synthesized in a straightforward manner. The in vitro cytotoxic activities were examined, and the most potent analogs induced considerably growth inhibition in the range of 1.5–6.7µM.

Synthesis of stemofoline analogues as acetylcholinesterase inhibitors

Thirty-two new stemofoline analogues were prepared from didehydrostemofoline for studies as AChE inhibitors. C-3 Side-chain modified amino, carbamate, triazole and oxazole stemofoline derivatives were prepared. In general the amine derivatives were found to be stronger inhibitors of AChE than their alcohol analogues that we previously reported. Compounds 5 and 26, with small C-3 side-chain substituents, were two of the most active inhibitors. Preliminary molecular docking studies suggested that these compounds may inhibit AChE by binding horizontally along the passage of the active-site gorge and block access to acetylcholine.

Structural basis for alcohol modulation of a pentameric ligand-gated ion channel

Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the "linking tunnel." These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member.

Synthesis of the orthogonally protected amino alcohol Phaol and analogs

The development of a multigram synthesis of the orthogonally protected amino acid-derived Phaol [2-{[(2S)-2-amino-3-phenylpropyl]amino}ethanol] is described. The goal of this work is to synthesize an orthogonally protected Phaol in a multigram scale up to 10 g (Cbz-Phaol), so it can be used in solution-based peptide synthesis of peptaibols. Two synthetic schemes were proposed and examined. Between the reduction-coupling and the coupling-reduction scheme, the latter gave the best results. A two-step synthesis affords easily purifiable products. Several analogs were synthesized using this methodology. All the molecules were orthogonally protected, so that they can be used in peptide synthesis. Deprotection posed no problems.

Distinct Chemoselectivities in the Platinum-Catalyzed 1,2-Carboalkoxylations of 5-Alkoxypent-1-yn-3-ol Derivatives

Two distinct Pt-catalyzed carboalkoxylations of alkynes are reported. The cycloisomerization of 5-alkoxypent-1-yn-3-ol derivatives 5 produces 2,6-dioxabicyclo[3.1.0]hexanes 6; the mechanism is postulated to involve a hydroxyl-triggered [3.3]-sigmatropic allyl rearrangement. As the same catalysis is extensible to their tertiary alcohol analogues 7, distinct dihydrofuranyl alcohols 8 were obtained through a [3.3]-allyl rearrangement that is not assisted by the hydroxyl group.

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)benzocycloalkanones, bromopropiophenones, and their alcohol analogs

A new series of substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl) benzocycloalkanones, bromopropiophenones, and their alcohol analogs were synthesized. The corresponding alcohols may act as potential allosteric modulators of GABA_B receptors.

Extraction of ethanol with higher carboxylic acid solvents and their toxicity to yeast

In a screening exercise for ethanol-selective extraction solvents, partitioning of ethanol and water from a 5 wt% aqueous solution into several C8–C18 carboxylic acids was studied. Results for the acids are compared with those from alcohols of similar structure. In all cases studied, the acids exhibited higher separation factor, but lower capacity than their alcohol analogs. Solvent toxicity to a commercial yeast commonly used in fuel ethanol production was evaluated for selected solvents. For the acids studied, those containing 12 or fewer carbons were toxic or inhibitory to the yeast; those containing 16 or more carbons were non-toxic and non-inhibitory.

4-(3-Aryloxyaryl)quinoline sulfones are potent liver X receptor agonists

A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.

Characterization and Pharmacology of the GHB Receptor

Radioligand binding using [(3)H]NCS-382, an antagonist of the GHB receptor, revealed specific binding sites in the rat cerebrocortical and hippocampal membranes. Scatchard analysis of saturation isotherms revealed two different populations of binding sites. NCS-382 was about 10 times more potent than GHB in inhibiting [(3)H]NCS-382 binding. A variety of ligands for other receptors did not affect [(3)H]NCS-382 binding. Quantitative autoradiographic analysis of [(3)H]NCS-382 binding revealed similar characteristics. Thus [(3)H]NCS-382, being more potent and selective, offers advantage over [(3)H]GHB as a radioligand. Unlike GHB, several analogues of GHB such as UMB68 (a tertiary alcohol analogue of GHB), UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), UMB66 (3-chloropropanoic acid), gamma-hydroxyvaleric acid (that is, GHV, a 4-methyl-substituted analogue of GHB), 3-HPA (3-hydroxyphenylacetic acid), and ethers of 3-hydroxyphenylacetic acid (UMB108, UMB109, and UMB119) displaced [(3)H]NCS-382 without affecting [(3)H]GABA binding to GABA(B) receptor. Thus these compounds offer an advantage over GHB as an experimental tool. Our study, aimed at exploring the potential involvement of the GHB receptor in the pharmacology of ethanol, indicated that ethanol does not affect [(3)H]NCS-382 binding in the rat brain, thereby suggesting that ethanol does not interact directly with the GHB receptor. Our study, aimed at exploring the involvement of the GHB receptor in the pathology of succinate semialdehyde dehydrogenase deficiency, which is known to cause elevation of GHB levels, revealed no change in the affinity, receptor density or displacement potency as determined by using [(3)H]NCS-382 as a radioligand in Aldh5a1(-/-) vs. Aldh5a1(+/+) mouse brain.

THE ROLE OF N265 OF THE GABAA RECEPTOR β2 SUBUNIT IN THE ACTIONS OF ALCOHOLS AND ANESTHETICS

Alcohols and volatile anesthetics enhance the function of γ‐aminobutyric acid type A (GABAA) receptors containing α, β, and γ subunits, and the presence of an alcohol and volatile anesthetic binding site has been identified in the α1, α2, and β1 subunits. However, the specific role of the β2 subunit has not been elucidated. The present study examined whether amino acid residue Asparagine‐265 (N265), which is homologous to the implicated residue in the α subunits, contributes to an alcohol and volatile anesthetic binding site in the GABAA receptor β2 subunit. Cysteine was substituted at the candidate residue, and cRNAs encoding wild‐type α1β2γ2S or mutant α1β2(N265C)γ2S receptors were injected into Xenopus laevis oocytes. Using two‐electrode voltage clamp electrophysiology, we asked whether the cysteine mutation affected receptor sensitivity to alcohols, and if octyl methanethiosulfonate (OMTS), an alcohol and anesthetic analog, reacted with the substituted cysteine and irreversibly altered GABA‐induced currents. Further, the potentiation of GABA‐induced currents by alcohols and anesthetics was measured before and after the application of OMTS, which has been shown to convalently bind to cysteine residues located at alcohol and anesthetic binding sites. We found that potentiation of GABA‐induced currents by butanol or octanol was significantly reduced in mutant 1β2(N265C)γ2S receptors compared to wild‐type receptors, and submaximal GABA‐induced currents of mutant receptors were irreversibly potentiated following the application of OMTS, presumably due to the covalent reaction between OMTS and the thiol group in the substituted cysteine. Moreover, the potentiation of GABA‐induced currents by butanol or isoflurane was abolished in mutant receptors following the application of OMTS, suggesting that an alcohol and volatile anesthetic binding site at position 265 of the β2 subunit was irreversibly occupied by OMTS and consequently prevented alcohols and anesthetics from binding and producing their effects. Taken together, our findings provide evidence that N265 may contribute to an alcohol and anesthetic binding site, and ultimately we propose that the GABAA receptor β2 subunit may be important for the actions of these compounds.

A New Pheromone Race of &lt;I&gt;Acrobasis nuxvorella&lt;/I&gt; (Lepidoptera: Pyralidae)

The sex pheromone of the monophagous Acrobasis nuxvorella Neunzig (Lepidoptera: Pyralidae) was reported as (9E,11Z)-hexadecadienal (9E,11Z-16:Ald) (Biorg. Med. Chem. 4: 331-339, 1996), and it has since been an effective integrated pest management (IPM) tool for monitoring this pest in the United States, but not in Mexico. Field and laboratory studies were conducted to confirm that the species in Mexico was indeed A. nuxvorella and to investigate the pheromone chemistry of the Mexican populations of this species. Initial field trials testing compounds structurally related to the known pheromone component, and blends thereof, indicated that a 100 microg:100 microg blend of (9E,11Z)-hexadecadien-1-yl acetate (9E,11Z-16:Ac):9E,11Z-16:Ald in rubber septa was effective in attracting male moths in Mexico. Coupled gas chromatography-electroantennogram analyses confirmed the presence of these compounds in extracts of pheromone glands of females, and antennae of male moths also responded to the alcohol analog (9E,11Z)-hexadecadien-1-ol (9E,11Z-16:OH). Subsequent field trials of various blends of these three compounds in Mexico showed that 1) both the acetate and aldehyde components were required for optimal attraction of male moths of the Mexican populations, and 2) addition of the alcohol suppressed attraction of males in a dose-dependent manner. Tests with the 1:1 9E,11Z-16:Ac:9E,11Z-16:Ald blend at various sites in the United States showed that this blend attracted some moths, but that moths attracted to 9E,11Z-16:Ald alone were predominant in the population. Furthermore, in preliminary studies the latter seemed not to respond to the blend. These findings indicate that there are two pheromone types of the pecan nut casebearer, and they have major implications for the direct use of these pheromones in pecan IPM.

A New Pheromone Race of Acrobasis nuxvorella (Lepidoptera: Pyralidae)

The sex pheromone of the monophagous Acrobasis nuxvorella Neunzig (Lepidoptera: Pyralidae) was reported as (9E,11Z)-hexadecadienal (9E,11Z-16:Ald) (Biorg. Med. Chem. 4: 331–339, 1996), and it has since been an effective integrated pest management (IPM) tool for monitoring this pest in the United States, but not in Mexico. Field and laboratory studies were conducted to confirm that the species in Mexico was indeed A. nuxvorella and to investigate the pheromone chemistry of the Mexican populations of this species. Initial field trials testing compounds structurally related to the known pheromone component, and blends thereof, indicated that a 100 μg:100 μg blend of (9E,11Z)-hexadecadien-1-yl acetate (9E,11Z-16:Ac):9E,11Z-16:Ald in rubber septa was effective in attracting male moths in Mexico. Coupled gas chromatography-electroantennogram analyses confirmed the presence of these compounds in extracts of pheromone glands of females, and antennae of male moths also responded to the alcohol analog (9E,11Z)-hexadecadien-1-ol (9E,11Z-16:OH). Subsequent field trials of various blends of these three compounds in Mexico showed that 1) both the acetate and aldehyde components were required for optimal attraction of male moths of the Mexican populations, and 2) addition of the alcohol suppressed attraction of males in a dose-dependent manner. Tests with the 1:1 9E,11Z-16:Ac:9E,11Z-16:Ald blend at various sites in the United States showed that this blend attracted some moths, but that moths attracted to 9E,11Z-16:Ald alone were predominant in the population. Furthermore, in preliminary studies the latter seemed not to respond to the blend. These findings indicate that there are two pheromone types of the pecan nut casebearer, and they have major implications for the direct use of these pheromones in pecan IPM.

Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: Implications for an animal model of autism

Environmental, dietary, and gastrointestinal factors may contribute to autism spectrum disorders (ASD). Propionic acid (PPA) is a short chain fatty acid, a metabolic end-product of enteric bacteria in the gut, and a common food preservative. Recent evidence indicates that PPA can cause behavioral abnormalities and a neuroinflammatory response in rats. Social behavior was examined in similarly-treated pairs of adult male Long-Evans rats placed in an open field following intracerebroventricular (ICV) injection of PPA (4 μl of 0.26 M solution) or control compounds. Behavior was analyzed using both the EthoVision behavior tracking system and by blind scoring of videotapes of social behaviors. Compared to controls, rats treated with PPA displayed social behavior impairments as indicated by significantly greater mean distance apart, reduced time spent in close proximity, reduced playful interaction, and altered responses to playful initiations. Treatment with another short chain fatty acid, sodium acetate, produced similar impairments, but treatment with the alcohol analog of PPA, 1-propanol, did not produce impairments. Immunohistochemical analysis of brain tissue taken from rats treated with PPA revealed reactive astrogliosis, indicating a neuroinflammatory response. These findings suggest that PPA can change both brain and behavior in the laboratory rat in a manner that is consistent with symptoms of human ASD.

Bicyclo[2.2.2]octane analogues of patchouli alcohol by Sakurai reaction and Nagata cyclization. Synthesis and olfactory properties of novel isopropyl derivatives

The synthesis of bicyclo(2.2.2)octane patchouli alcohol analogues by the Sakurai conjugate addition and Nagata cyclization is described. By this approach, complementary to those so far adopted and based on the Diels-Alder addition, known analogues 2, 3 and 20 and new analogues 8-11, with 1-isopropylbicyclo(2.2.2)octane structure, could be obtained. The olfactory properties of 8 and 10 were also evaluated.

Synthesis of some tropane derivatives of anticipated activity on the reuptake of norepinephrine and/or serotonin

A variety of tropane derivatives 14a–g were prepared via the reaction of the alcohol analogs 12a and 12b with substituted fluorobenzenes 13a–f. The prepared compounds were tested for their activity and selectivity toward the norepinephrine transporter (NET) and serotonin transporter (SERT) using yohimbine-induced mortality and 5-hydroxytryptophan-induced neurotoxicity in mice, respectively. All the tested compounds were found to be NE and 5-HT reuptake inhibitors except 14d which exhibited selective 5-HT reuptake inhibition activity.

Synthesis and antiproliferative activity of novel sugiol β-amino alcohol analogs

A series of β-amino alcohol analogs of sugiol were synthesized in a straightforward manner. The in vitro antiproliferative activities were examined in the human solid tumor cell lines A2780, SW1573 and WiDr. The most potent analogs induced considerably growth inhibition in the range 1.5–6.7 μM. The results showed that β-amino alcohol analogs are more potent than the parent compound. In addition, the derivatives with secondary amine fragments showed more active than those bearing tertiary amines.

Synthesis and Evaluation of 1-Deoxy-d-xylulose 5-Phosphate Analogues as Chelation-Based Inhibitors of Methylerythritol Phosphate Synthase

[structures: see text] A series of 1-deoxy-D-xylulose 5-phosphate (DXP) analogues were synthesized and evaluated as inhibitors of E. coli methylerythritol phosphate (MEP) synthase. In analogues 1-4, the methyl group in DXP was replaced by hydroxyl, hydroxylamino, methoxy, and amino moieties, respectively. In analogues 5 and 6, the acetyl moiety in DXP was replaced by hydroxymethyl and aminomethyl groups. These compounds were designed to coordinate to the active site divalent metal in MEP synthase. The carboxylate (1), methyl ester (3), amide (4), and alcohol (5) analogues were inhibitors with IC50's ranging from 0.25 to 1.0 mM. The hydroxamic acid (2) and amino (6) analogues did not inhibit the enzyme.