Synthesis and Characterization of Coelenterazine Analogs

The synthesis of the compounds started with the functionalization of commercial bromopyrazin-2-amine either with a bromine or iodine atom. A subsequent reaction of the resulting para-substituted aminopyrazines Br-Clm-9 or Br-Clm-11 with N-bromosuccinimide in ethanol provided the homo-(Br-Clm-10) or the hetero-dihalogenated products, respectively. Coelenteramines Br-Clm-1/3/5/7/8 were obtained after the Suzuki–Miyaura cross-coupling of the corresponding functionalized aminopyrazines with commercial boronic acids using bis(triphenylphosphine)palladium (II) dichloride as the palladium source and potassium carbonate as the base. Compounds Br-Clm-2, Br-Clm-4, and Br-Clm-6 were obtained after halogenation of Coelenteramines Br-Clm-1, Br-Clm-3, and Br-Clm-5 in standard conditions, respectively. Synthetic Coelenteramide Br-Clmd was synthesized through N-acetylation of Br-Clm using pyridine as the base to avoid the formation of the disubstituted subproduct. Precursors of the initial Coelenterazine derivatives Br-Cla-1/2/3, OH-Cla, and Br-Clm-1 were synthesized from pyrazin-2-amine in a similar manner, following the procedures described in [12 (link),13 (link),14 (link)]. Then, the imidazopyrazinone core was formed after condensation of the corresponding Coelenteramines with a 1,2-dicarbonylic fragment (methyl glyoxal) [12 (link),13 (link),14 (link)]. This route has been repeatedly used as the main synthetic path for the obtention of Coelenterazine analogs and derivatives since it goes through stable intermediates, provides the desired compounds in high yields, and is compatible with a great variety of functional groups. The structural characterization was performed using ¹H- and ¹³C-NMR spectroscopy as well as FT-MS spectrometry. Br-Cla-1/2/3, OH-Cla, and Br-Clm-1/3 have already been described in the literature [12 (link),13 (link),14 (link)], Br-Clm-9 and Br-Clm-10 are commercially available, and further details for the compounds Br-Clmd and Br-Clm-1/2/4/5/6/7/8/11 can be found in the Supplementary Materials.

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González-Berdullas P., Pereira R.B., Teixeira C., Silva J.P., Magalhães C.M., Rodríguez-Borges J.E., Pereira D.M., Esteves da Silva J.C, & Pinto da Silva L. (2022). Discovery of the Anticancer Activity for Lung and Gastric Cancer of a Brominated Coelenteramine Analog. International Journal of Molecular Sciences, 23(15), 8271.

Publication 2022

13c nmr Acetylation Amine Boronic acids Bromine Bromosuccinimide Coelenteramide Coelenterazine Derivatives Ethanol Halogenation Homo Iodine Methyl glyoxal Nmr spectroscopy Palladium Palladium dichloride Potassium carbonate Pyridine Spectrometry Spectroscopy Triphenylphosphine

Corresponding Organization : Rede de Química e Tecnologia

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Variable analysis

independent variables

Functionalization of commercial bromopyrazin-2-amine with bromine or iodine atom
Reaction of the resulting para-substituted aminopyrazines Br-Clm-9 or Br-Clm-11 with N-bromosuccinimide in ethanol
Suzuki–Miyaura cross-coupling of the corresponding functionalized aminopyrazines with commercial boronic acids using bis(triphenylphosphine)palladium (II) dichloride and potassium carbonate
Halogenation of Coelenteramines Br-Clm-1, Br-Clm-3, and Br-Clm-5 in standard conditions
N-acetylation of Br-Clm using pyridine as the base

dependent variables

Formation of homo- (Br-Clm-10) or hetero-dihalogenated products
Synthesis of Coelenteramines Br-Clm-1/3/5/7/8
Synthesis of Compounds Br-Clm-2, Br-Clm-4, and Br-Clm-6
Synthesis of Synthetic Coelenteramide Br-Clmd
Synthesis of Precursors of the initial Coelenterazine derivatives Br-Cla-1/2/3, OH-Cla, and Br-Clm-1
Formation of the imidazopyrazinone core after condensation of the corresponding Coelenteramines with a 1,2-dicarbonylic fragment (methyl glyoxal)

control variables

Ethanol as the solvent for the reaction with N-bromosuccinimide
Bis(triphenylphosphine)palladium (II) dichloride as the palladium source and potassium carbonate as the base for the Suzuki–Miyaura cross-coupling
Pyridine as the base for the N-acetylation of Br-Clm to avoid the formation of the disubstituted subproduct

positive controls

Br-Cla-1/2/3, OH-Cla, and Br-Clm-1/3 have already been described in the literature

negative controls

Br-Clm-9 and Br-Clm-10 are commercially available

Annotations

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