68062-88-4Relevant articles and documents
BIOMARKER PANEL TARGETED TO DISEASES DUE TO MULTIFACTORIAL ONTOLOGY OF GLYCOCALYX DISRUPTION
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Paragraph 0284; 0285, (2021/04/02)
The present disclosure provides biomarkers useful as companion diagnostics for detecting glycocalyx-based disease that is amenable to treatment using compounds designed for improving the condition of the glycocalyx and/or reducing inflammation and/or oxidative damage, as well as related compositions, kits, and methods.
Mutasynthesis of Physostigmines in Myxococcus xanthus
Winand, Lea,Schneider, Pascal,Kruth, Sebastian,Greven, Nico-Joel,Hiller, Wolf,Kaiser, Marcel,Pietruszka, J?rg,Nett, Markus
supporting information, p. 6563 - 6567 (2021/08/30)
The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach that merged chemical synthesis with pathway refactoring, we produced a series of physostigmine analogues with altered specificity and toxicity profiles in the heterologous host Myxococcus xanthus. The compounds that were generated by applying a simple feeding strategy include the promising drug candidate phenserine, which was previously accessible only by total synthesis.
Biocatalytic C3-Indole Methylation—A Useful Tool for the Natural-Product-Inspired Stereoselective Synthesis of Pyrroloindoles
Schneider, Pascal,Hen?en, Birgit,Paschold, Beatrix,Chapple, Benjamin P.,Schatton, Marcel,Seebeck, Florian P.,Classen, Thomas,Pietruszka, J?rg
supporting information, p. 23412 - 23418 (2021/09/20)
Enantioselective synthesis of bioactive compounds bearing a pyrroloindole framework is often laborious. In contrast, there are several S-adenosyl methionine (SAM)-dependent methyl transferases known for stereo- and regioselective methylation at the C3 position of various indoles, directly leading to the formation of the desired pyrroloindole moiety. Herein, the SAM-dependent methyl transferase PsmD from Streptomyces griseofuscus, a key enzyme in the biosynthesis of physostigmine, is characterized in detail. The biochemical properties of PsmD and its substrate scope were demonstrated. Preparative scale enzymatic methylation including SAM regeneration was achieved for three selected substrates after a design-of-experiment optimization.
Mechanistic and structural analysis of Drosophila melanogaster arylalkylamine N-acetyltransferases
Dempsey, Daniel R.,Jeffries, Kristen A.,Bond, Jason D.,Carpenter, Anne-Marie,Rodriguez-Ospina, Santiago,Breydo, Leonid,Caswell, K. Kenneth,Merkler, David J.
, p. 7777 - 7793 (2015/02/19)
(Chemical Equation Presented). Arylalkylamine N-acetyltransferase (AANAT) catalyzes the penultimate step in the biosynthesis of melatonin and other N-acetylarylalkylamides from the corresponding arylalkylamine and acetyl-CoA. The N-acetylation of arylalkylamines is a critical step in Drosophila melanogaster for the inactivation of the bioactive amines and the sclerotization of the cuticle. Two AANAT variants (AANATA and AANATB) have been identified in D. melanogaster , in which AANATA differs from AANATB by the truncation of 35 amino acids from the N-terminus. We have expressed and purified both D. melanogaster AANAT variants (AANATA and AANATB) in Escherichia coli and used the purified enzymes to demonstrate that this N-terminal truncation does not affect the activity of the enzyme. Subsequent characterization of the kinetic and chemical mechanism of AANATA identified an ordered sequential mechanism, with acetyl-CoA binding first, followed by tyramine. We used a combination of pH-activity profiling and site-directed mutagenesis to study prospective residues believed to function in AANATA catalysis. These data led to an assignment of Glu-47 as the general base in catalysis with an apparent pKa of 7.0. Using the data generated for the kinetic mechanism, structure-function relationships, pH-rate profiles, and site-directed mutagenesis, we propose a chemical mechanism for AANATA.
N-acetyl-5-arylalkoxytryptamine analogs: Probing the melatonin receptors for MT1-selectivity
Markl, Christian,Clafshenkel, William P.,Attia, Mohamed I.,Sethi, Shalini,Witt-Enderby, Paula A.,Zlotos, Darius P.
experimental part, p. 666 - 674 (2012/06/17)
A series of melatonin analogs obtained by the replacement of the ether methyl group with larger arylalkyl and aryloxyalkyl substituents was prepared in order to probe the melatonin receptors for MT1-selectivity. The most MT1-selective agents 11 and 15 were substituted with a Ph(CH 2)3 or a PhO(CH2)3 group. Compounds 11 and 15 displayed 11.5-fold and 11-fold higher affinity for the MT1 receptors than for the MT2 subtype. Interestingly, in our binding assay 11 and 15 have shown considerably higher MT1-affinity and selectivity than the reference ligand, the dimeric agomelatine 1a. The synthesis and pharmacological evaluation of a novel series of MLT analogs obtained by replacing the ether methyl group with arylalkyl and aryloxyalkyl moieties is described here. The results indicate for compounds 11 and 15 considerably higher MT1-affinity and selectivity than the reference ligand, the dimeric agomelatine 1a. Copyright
Structure-activity relationships for substrates and inhibitors of pineal 5-hydroxytryptamine-N-acetyltransferase: Preliminary studies
Shen, Shuren,Bremont, Beatrice,Serraz, Isabelle,Andrieux, Jean,Poncet, Annie,Mathe-Allainmat, Monique,Chanut, Evelyne,Trouvin, Jean-Hugues,Langlois, Michel
, p. 133 - 140 (2007/10/03)
Tryptamine, (1-naphthyl)ethylamine and phenethylamine derivatives were tested as substrates of ovine pineal serotonin-N-acetyl transferase (5-HT-NAT), a key enzyme involved in the synthesis of melatonin. Almost all of the indole derivatives possessed affinity similar to that of tryptamine (K(m) - 0.05 mM), while the substituted naphthalene and phenyl derivatives were less potent. However, the K, values seem be influenced by the steric hindrance and polar properties of the substituent. V(max) values for the naphthyl and phenyl derivatives were generally 10-20-fold higher than those of the indole derivatives and no clear structure-activity relationship was observed. Melatonin and several bioisoteric derivatives were shown to be inhibitors of 5-HT-N-acetyltransferase. Preliminary data suggested that over the 5-50-μM concentration range, melatonin was a competitive inhibitor (IC50 = 10 μM) with a concentration-dependent inhibitory effect on its own synthesis in the pineal gland. However, the bioisosteric naphthalene derivatives were characterized instead as mixed inhibitors. (1-Napthyl)ethylacetamido, a putative melatoninergic antagonist, was also shown to be an inhibitor of 5-HT-N-acetyltransferase (IC50 = 8 μM) and is a promising tool for the regulation of melatonin synthesis and the understanding of its role.
Binding of O-alkyl derivatives of serotonin at human 5-HT1Dβ receptors
Glennon, Richard A.,Hong, Seoung-Soo,Bondarev, Mikhail,Law, Ho,Dukat, Malgorzata,Rakhit, Suman,Power, Patricia,Fan, Ermei,Kinneau, Diana,Kamboj, Rajender,Teitler, Milt,Herrick-Davis, Katharine,Smith, Carol
, p. 314 - 322 (2007/10/03)
In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1Dβ receptors (K(i) 300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1Dβ K(i) = 2.3 nM) but with greater (i.e., 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or β- carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1Dβ versus 5-HT1Dα sites; nevertheless, compounds 10 (recently shown to behave as a 5- HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.
