Synthesis and Fluorescence Properties of 4-Cyano and 4-Formyl Melatonin as Putative Melatoninergic Ligands

Fluorescent ligands are imperative to many facets of chemical biology and medicinal chemistry. Herein, we report the syntheses of two fluorescent melatonin-based derivatives as potential ligands of melatonin receptors. The two compounds, namely, 4-cyano and 4-formyl melatonin (4CN-MLT and 4CHO-MLT, respectively), which differ from melatonin by only two/three atoms that are very compact in size, were prepared using the selective C3-alkylation of indoles with N-acetyl ethanolamines involving the “borrowing hydrogen” strategy. These compounds exhibit absorption/emission spectra that are red-shifted from those of melatonin. Binding studies on two melatonin receptor subtypes showed that these derivatives have a modest affinity and selectivity ratio.

[1]  M. Vendrell,et al.  Miniaturized Chemical Tags for Optical Imaging , 2022, Angewandte Chemie.

[2]  F. Gai,et al.  Synthesis and Characterization of the Fluorescence Utility of Two Visible-Light-Absorbing Tryptophan Derivatives , 2022, Chemical Physics Letters.

[3]  F. Gai,et al.  Tryptophan as a Template for Development of Visible Fluorescent Amino Acids. , 2021, The journal of physical chemistry. B.

[4]  S. Munck,et al.  Lighting up the plasma membrane: Development and applications of fluorescent ligands for transmembrane proteins. , 2021, Chemistry.

[5]  Amos B. Smith,et al.  Tuning the electronic transition energy of indole via substitution: application to identify tryptophan-based chromophores that absorb and emit visible light. , 2021, Physical chemistry chemical physics : PCCP.

[6]  T. Donohoe,et al.  Hydrogen‐Borrowing Alkylation of 1,2‐Amino Alcohols in the Synthesis of Enantioenriched γ‐Aminobutyric Acids , 2021, Angewandte Chemie.

[7]  J. Boutin,et al.  Melatonin controversies, an update , 2020, Journal of pineal research.

[8]  C. Sotriffer,et al.  Melatonin receptor ligands: A pharmaco‐chemical perspective , 2020, Journal of pineal research.

[9]  G. Piersanti,et al.  C3-Alkylation of indoles and oxindoles by alcohols by means of borrowing hydrogen methodology , 2020 .

[10]  S. Pramanik,et al.  Correction to Small Molecule as Fluorescent Probes for Monitoring Intracellular Enzymatic Transformations. , 2020, Chemical reviews.

[11]  W. DeGrado,et al.  Synthesis and application of the blue fluorescent amino acid l-4-cyanotryptophan to assess peptide-membrane interactions. , 2019, Chemical communications.

[12]  Reid H. J. Olsen,et al.  Structural insights into lipid and ligand regulation of serotonin receptors , 2019, Nature.

[13]  Reid H. J. Olsen,et al.  XFEL structures of the human MT2 melatonin receptor reveal basis of subtype selectivity , 2019, Nature.

[14]  F. Arnold,et al.  Improved Synthesis of 4-Cyanotryptophan and Other Tryptophan Analogues in Aqueous Solvent Using Variants of TrpB from Thermotoga maritima. , 2018, The Journal of organic chemistry.

[15]  Oxana V. Baranova,et al.  Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release , 2017, Proceedings of the National Academy of Sciences.

[16]  R. Gerbier,et al.  Design and validation of the first cell‐impermeant melatonin receptor agonist , 2017, British journal of pharmacology.

[17]  W. DeGrado,et al.  Blue fluorescent amino acid for biological spectroscopy and microscopy , 2017, Proceedings of the National Academy of Sciences.

[18]  G. Piersanti,et al.  A simple, modular synthesis of C4-substituted tryptophan derivatives. , 2016, Organic & biomolecular chemistry.

[19]  P. Delagrange,et al.  Design, synthesis and biological evaluation of fluorescent ligands for MT1 and/or MT2 melatonin receptors , 2016 .

[20]  Juyoung Yoon,et al.  Recent progress in the development of fluorescent, luminescent and colorimetric probes for detection of reactive oxygen and nitrogen species. , 2016, Chemical Society reviews.

[21]  G. Piersanti,et al.  Observations concerning the synthesis of tryptamine homologues and branched tryptamine derivatives via the borrowing hydrogen process: synthesis of psilocin, bufotenin, and serotonin , 2016 .

[22]  S. Benkovic,et al.  Cyanotryptophans as Novel Fluorescent Probes for Studying Protein Conformational Changes and DNA-Protein Interaction. , 2015, Biochemistry.

[23]  D. Sugden,et al.  New coumarin-based fluorescent melatonin ligands. Design, synthesis and pharmacological characterization. , 2015, European journal of medicinal chemistry.

[24]  C. Mirkin,et al.  Nanoparticle Probes for the Detection of Cancer Biomarkers, Cells, and Tissues by Fluorescence. , 2015, Chemical reviews.

[25]  Chen-Ho Tung,et al.  Design strategies of fluorescent probes for selective detection among biothiols. , 2015, Chemical Society reviews.

[26]  G. Piersanti,et al.  Iridium-catalyzed direct synthesis of tryptamine derivatives from indoles: exploiting n-protected β-amino alcohols as alkylating agents. , 2015, The Journal of organic chemistry.

[27]  Khai Tran,et al.  Excited State Photoreaction between the Indole Side Chain of Tryptophan and Halocompounds Generates New Fluorophores and Unique Modifications , 2014, Photochemistry and photobiology.

[28]  Zhao Ma,et al.  Toward fluorescent probes for G-protein-coupled receptors (GPCRs). , 2014, Journal of medicinal chemistry.

[29]  P. Delagrange,et al.  Original Design of Fluorescent Ligands by Fusing BODIPY and Melatonin Neurohormone. , 2014, ACS medicinal chemistry letters.

[30]  D. Jakobs,et al.  Ligands for fluorescence correlation spectroscopy on g protein-coupled receptors. , 2012, Current medicinal chemistry.

[31]  A. Goddard,et al.  Contributions of fluorescence techniques to understanding G protein-coupled receptor dimerisation , 2012, Biophysical Reviews.

[32]  M. Mor,et al.  Melatonin Receptor Agonists: New Options for Insomnia and Depression Treatment , 2011, CNS neuroscience & therapeutics.

[33]  J. Pin,et al.  Original Fluorescent Ligand-Based Assays Open New Perspectives in G-Protein Coupled Receptor Drug Screening , 2011, Pharmaceuticals.

[34]  Y. Tor,et al.  Fluorescent analogs of biomolecular building blocks: design, properties, and applications. , 2010, Chemical reviews.

[35]  Ilka Böhme,et al.  Illuminating the life of GPCRs , 2009, Cell Communication and Signaling.

[36]  K. Kuder,et al.  Fluorescent GPCR ligands as new tools in pharmacology. , 2008, Current medicinal chemistry.

[37]  J. Atkinson,et al.  Therapeutic Perspectives for Melatonin Agonists and Antagonists , 2003, Journal of neuroendocrinology.

[38]  Corwin Hansch,et al.  A survey of Hammett substituent constants and resonance and field parameters , 1991 .

[39]  M. Meyer,et al.  Ergoline synthons. 2. Synthesis of 1,5-dihydrobenz[cd]indol-4(3H)-ones and 1,3,4,5-tetrahydrobenz[cd]indol-4-amines , 1984 .

[40]  M. Meyer,et al.  Ergoline synthons: Synthesis of 3,4-dihydro-6-methoxybenz[cd]indol-5(1H)-one (6-methoxy-Uhle's ketone) and 3,4-dihydrobenz[cd]indol-5(1H)-one (Uhle's ketone) via a novel decarboxylation of indole-2-carboxylates , 1984 .

[41]  M. Meyer,et al.  ERGOLINE SYNTHONS: SYNTHESIS OF 3,4-DIHYDRO-6-METHOXYBENZ(CD)INDOL-5(1H)-ONE (6-METHOXY-UHLE′S KETONE) AND 3,4-DIHYDROBENZ(CD)INDOL-5(1H)-ONE (UHLE′S KETONE) VIA A NOVEL DECARBOXYLATION OF INDOLE-2-CARBOXYLATES , 1985 .