synthesis-ph-dependent-pyrazole-imidazole-isoindolone-dipyrrinone

Synthesis of pH Dependent Pyrazole, Imidazole, and Isoindolone Dipyrrinone Fluorophores using a Claisen-Schmidt Condensation Approach

Methine-bridged conjugated bicyclic aromatic compounds are common constituents of a range of biologically relevant molecules such as porphyrins, ...

Nevada State College

A three-pot synthesis oriented for an undergraduate organic chemistry laboratory was developed to construct a fluorescent acridone molecule. This laboratory experiment utilizes Grignard addition to an aldehyde, alcohol oxidation, and iterative nucleophilic aromatic substitution steps to produce the final product. Each of the intermediates and the acridone product of the synthesis are analyzed by common techniques available in most undergraduate chemistry laboratories, such as melting point, TLC, IR spectroscopy, UV-Vis spectroscopy, and fluorescence spectroscopy. Yields for each transformation in the synthesis are generally moderately low to good (20-90%) and nearly all of the students (>90%) who attempted the synthesis were able to produce the final acridone product.

Synthesis of a Fluorescent Acridone using a Grignard Addition, Oxidation, and Nucleophilic Aromatic Substitution Reaction Sequence.

A practical and convenient procedure for the nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine was developed using a hydroxide assisted, thermal decomposition of N,N-dimethylforamide. These conditions are tolerant of nitro, nitrile, aldehyde, ketone, and amide groups but will undergo acyl substitution to form amides for methyl esters and acyl chlorides. Isolated yields of the products range from 44 - 98%, with the majority being greater than 70% for seventeen examples.

A General Method for Nucleophilic Aromatic Substitution of Aryl Fluorides and Chlorides with Dimethylamine using Hydroxide-Assisted Decomposition of N,N-Dimethylforamide.

Dipyrrinones are nonfluorescent yellow-pigmented constituents of bilirubin that undergo Z to E isomerization when excited with UV/blue light. Mechanical restriction of the E/Z isomerization process results in highly fluorescent compounds such as ,-methylene-bridged dipyrrinones and xanthoglows. This manuscript describes the first examples of dipyrrinone analogues, which exhibit fluorescence without covalently linking the pyrole-pyrrolidine nitrogen atoms. Instead these analogues restrict E/Z isomerization through intramolecular hydrogen bonding, resulting in mild to moderately fluorescent compounds (Φ = 0.01-0.30). Further, in basic solutions (pH > 12), the dipyrrinone analogues readily deprotonate and absorption/emission profiles of the fluorophores red-shifts by 10-49 nm. Directly from commercial materials, 10 analogues were prepared in 41-96% yields in one step. To estimate the capacity of which intramolecular hydrogen bonding has upon restricting the E/Z isomerization process, conformational energies of all analogues, in both the protonated and deprotonated species, were explored by using quantum-mechanical density functional theory (DFT) and time-dependent DFT calculations. The computed strengths of the intramolecular hydrogen bonds are related to the barriers of rotation about the 5-6 bond and both correlate with the experimentally measured fluorescence quantum yields.

Pyrazole, Imidazole, and Isoindolone Dipyrrinone Analogues: pH-Dependent Fluorophores That Red-Shift Emission Frequencies in a Basic Solution.

Ser/Thr protein phosphatases (PPs) regulate a substantial range of cellular processes with protein phosphatases 1 (PP1) and 2 A (PP2A) accounting for over 90 % of the activity within cells. Nevertheless, tools to study PPs are limited as PPs inhibitors, particularly those selective for PP1 inhibition, are relatively scarce. Two examples of PP1-selective inhibitors, which share structural similarities, are tautomycin (TTM) and tautomycetin (TTN). This work describes the development of PP1/PP2A inhibitors that incorporate key structural features of TTM and TTN and are designed to conserve regions known to bind the active site of PP1/PP2A but vary regions that differentially contact the hydrophobic groove of PP1/PP2A. In all 28 TTN analogues were synthetically generated that inhibit PP1/PP2A activity at <250 mM; seven possessed inhibition activity at 100 nM. The IC values were determined for the seven most active analogues, which ranged from 34 to 1500 nM (PP1) and 70 to 6800 nM (PP2A). Four of the seven analogues possessed PP1 selectivity, and one demonstrated eightfold selectivity in the nanomolar range (PP1 IC =34 nM, PP2A IC =270 nM). A rationale is given for the observed differences in selectivity.

Article	Year
Synthesis of a Fluorescent Acridone using a Grignard Addition, Oxidation, and Nucleophilic Aromatic Substitution Reaction Sequence. Journal of chemical education\| PubMed ID: 27681671	2015
A General Method for Nucleophilic Aromatic Substitution of Aryl Fluorides and Chlorides with Dimethylamine using Hydroxide-Assisted Decomposition of N,N-Dimethylforamide. Synthetic communications\| PubMed ID: 27688484	2016
Pyrazole, Imidazole, and Isoindolone Dipyrrinone Analogues: pH-Dependent Fluorophores That Red-Shift Emission Frequencies in a Basic Solution. The Journal of organic chemistry\| PubMed ID: 31438666	2019
Tautomycetin Synthetic Analogues: Selective Inhibitors of Protein Phosphatase I. ChemMedChem\| PubMed ID: 33301228	2021

Zachary R. Woydziak

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