6-Hydroxyindole

Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG.[Pubmed:27096041]

ACS Med Chem Lett. 2016 Mar 16;7(4):357-62.

Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6-5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-Hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds.

Borondipyrromethene-derived Cu2+ sensing chemodosimeter for fast and selective detection.[Pubmed:22402504]

Org Biomol Chem. 2012 Apr 21;10(15):3104-9.

Here, we report a new Cu(2+)-selective fluorescent turn-on probe BODIPY-EP, in which the 2-pyridinecarboxylic acid is connected to a 6-Hydroxyindole-based BODIPY platform through an ester linkage. The ester bond of BODIPY-EP is selectively hydrolyzed by the reaction with Cu(2+) under mild and neutral conditions to generate BODIPY-OH, showing strong characteristic fluorescence of BODIPY-OH. The favorable features of BODIPY-EP towards Cu(2+) include fast response, large fluorescence enhancement and high selectivity. We further demonstrated that the membrane-permeable probe reacts with intracellular Cu(2+) and exhibits bright fluorescence in living cells.

The Biosynthetic Pathway of Indole-3-Carbaldehyde and Indole-3-Carboxylic Acid Derivatives in Arabidopsis.[Pubmed:24728709]

Plant Physiol. 2014 Jun;165(2):841-853.

Indolic secondary metabolites play an important role in pathogen defense in cruciferous plants. In Arabidopsis (Arabidopsis thaliana), in addition to the characteristic phytoalexin camalexin, derivatives of indole-3-carbaldehyde (ICHO) and indole-3-carboxylic acid (ICOOH) are synthesized from tryptophan via the intermediates indole-3-acetaldoxime and indole-3-acetonitrile. Based on feeding experiments combined with nontargeted metabolite profiling, their composition in nontreated and silver nitrate (AgNO3)-treated leaf tissue was comprehensively analyzed. As major derivatives, glucose conjugates of 5-hydroxyindole-3-carbaldehyde, ICOOH, and 6-Hydroxyindole-3-carboxylic acid were identified. Quantification of ICHO and ICOOH derivative pools after glucosidase treatment revealed that, in response to AgNO3 treatment, their total accumulation level was similar to that of camalexin. ARABIDOPSIS ALDEHYDE OXIDASE1 (AAO1), initially discussed to be involved in the biosynthesis of indole-3-acetic acid, and Cytochrome P450 (CYP) 71B6 were found to be transcriptionally coexpressed with camalexin biosynthetic genes. CYP71B6 was expressed in Saccharomyces cerevisiae and shown to efficiently convert indole-3-acetonitrile into ICHO and ICOOH, thereby releasing cyanide. To evaluate the role of both enzymes in the biosynthesis of ICHO and ICOOH derivatives, knockout and overexpression lines for CYP71B6 and AAO1 were established and analyzed for indolic metabolites. The observed metabolic phenotypes suggest that AAO1 functions in the oxidation of ICHO to ICOOH in both nontreated and AgNO3-treated leaves, whereas CYP71B6 is relevant for ICOOH derivative biosynthesis specifically after induction. In summary, a model for the biosynthesis of ICHO and ICOOH derivatives is presented.

Safety assessment of 6-hydroxyindole as used in cosmetics.[Pubmed:25297906]

Int J Toxicol. 2014 Sep-Oct;33(3 Suppl):24S-35S.

The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 6-Hydroxyindole, which functions as an oxidative hair dye ingredient. The Panel considered relevant animal and human data provided in this safety assessment and concluded that 6-Hydroxyindole is safe for use in oxidative hair dye formulations.

Target-triggered deprotonation of 6-hydroxyindole-based BODIPY: specially switch on NIR fluorescence upon selectively binding to Zn2+.[Pubmed:22932912]

Chem Commun (Camb). 2012 Oct 11;48(79):9897-9.

Based on 6-Hydroxyindole BODIPY with a Schiff-base structure, NIR fluorescence with impressively high selectivity is triggered by deprotonation of the phenol group upon binding with Zn(2+) due to the chelation-enhanced fluorescence effect, thus realizing a promising application in bioimaging of Zn(2+).

Monitoring of urinary metabolites of JWH-018 and JWH-073 in legal cases.[Pubmed:23890611]

Forensic Sci Int. 2013 Sep 10;231(1-3):13-9.

Due to their cannabis-like effects, synthetic cannabinoids have attracted much public attention since 2008. Thus, elucidation of the metabolic pattern and the detection of the intake of these drugs have been of major concern. In order to suggest appropriate urinary biomarkers to prove JWH-018 or JWH-073 intake, we selected the major metabolites of JWH-018 and JWH-073, namely (omega)-, (omega-1)-hydroxy, carboxy and 6-Hydroxyindole metabolites, and validated a method for the quantification of these metabolites using solid-phase extraction based on LC-MS/MS analysis. Authentic urine specimens obtained from drug offenders were screened via a synthetic cannabinoid ELISA kit and were analyzed by LC-MS/MS for confirmation. Twenty-one out of a total of 52 samples (40%) were found positive for at least one metabolite of JWH-018 or JWH-073. N-pentyl hydroxy metabolites of JWH-018 and carboxy metabolites of JWH-018 and JWH-073 were detected in all positive samples. However, the rest of the metabolites were either not detected or only a small amount of them were found. A considerable variation was observed in the concentration ratio of (omega) and (omega-1)-hydroxy metabolites of JWH-018. Based on the results, it may have some pitfalls to determine the ingestion of specific synthetic cannabinoids by detecting a few metabolites, considering the continuous emergence of structurally related synthetic cannabinoids. Thus, use of synthetic cannabinoids should be proven carefully through comprehensive investigation of analytical results of biological specimens.

Targeting GluN2B-containing N-Methyl-D-aspartate receptors: design, synthesis, and binding affinity evaluation of novel 3-substituted indoles.[Pubmed:24862313]

Arch Pharm (Weinheim). 2014 Aug;347(8):533-9.

In an effort to improve our knowledge about structure-affinity relationships (SARs) for a class of 3-substituted-indole derivatives as GluN2B-containing N-methyl-D-aspartate-type receptor (NMDAR) ligands, we herein describe the design, synthesis, and preliminary screening of a new series of molecules. The in vitro determination of binding affinities suggested that 5-hydroxy- and 6-Hydroxyindole derivatives 12 and 13 were active ligands. Generally, the novel compounds proved to be less potent than their homologs previously reported as promising neuroprotective agents. In fact, our lead compound 3-(4-benzylpiperidin-1-yl)-1-(5-hydroxy-1H-indol-3-yl)ethan-1-one (2) was about 10-fold more active than the new propan-1-one derivative (12). To rationalize the low potency of the new analog 12, docking studies were also performed and the in silico results were consistent with the in vitro data.

A spectroscopic survey of substituted indoles reveals consequences of a stabilized 1Lb transition.[Pubmed:22882557]

Photochem Photobiol. 2013 Jan-Feb;89(1):40-50.

Although tryptophan is a natural probe of protein structure, interpretation of its fluorescence emission spectrum is complicated by the presence of two electronic transitions, (1)L(a) and (1)L(b). Theoretical calculations show that a point charge adjacent to either ring of the indole can shift the emission maximum. This study explores the effect of pyrrole and benzyl ring substitutions on the transitions' energy via absorption and fluorescence spectroscopy, and anisotropy and lifetime measurements. The survey of indole derivatives shows that methyl substitutions on the pyrrole ring effect (1)L(a) and (1)L(b) energies in tandem, whereas benzyl ring substitutions with electrophilic groups lift the (1)L(a)/(1)L(b) degeneracy. For 5- and 6-Hydroxyindole in cyclohexane, (1)L(a) and (1)L(b) transitions are resolved. This finding provides for (1)L(a) origin assignment in the absorption and excitation spectra for indole vapor. The 5- and 6-Hydroxyindole excitation spectra show that despite a blue-shifted emission spectrum, both the (1)L(a) and (1)L(b) transitions contribute to emission. Fluorescence lifetimes of 1(0) ns for 5-hydroxyindole are consistent with a charge acceptor-induced increase in the nonradiative rate (1).