Abstract
There has been much effort to exploit fluorescence techniques in the detection of nucleic acids. Canonical nucleic acids are essentially nonfluorescent; however, the modification of the nucleobase has proved to be a fruitful way to engender fluorescence. Much of the chemistry used to prepare modified nucleobases relies on expensive transition metal catalysts. In this work, we describe the synthesis of biaryl quinazolinone-uracil nucleobase analogs prepared by the condensation of anthranilamide derivatives and 5-formyluracil using inexpensive copper salts. A selection of modified nucleobases were prepared, and the effect of methoxy- or nitro- group substitution on the photophysical properties was examined. Both the dihydroquinazolinone and quinazolinone modified uracils have much larger molar absorptivity (~4–8×) than natural uracil and produce modest blue fluorescence. The quinazolinone-modified uracils display higher quantum yields than the corresponding dihydroquinazolinones and also show temperature and viscosity dependent emission consistent with molecular rotor behavior. Peptide nucleic acid (PNA) monomers possessing quinazolinone modified uracils were prepared and incorporated into oligomers. In the sequence context examined, the nitro-substituted, methoxy-substituted and unmodified quinazolinone inserts resulted in a stabilization (∆Tm = +4.0/insert; +2.0/insert; +1.0/insert, respectively) relative to control PNA sequence upon hybridization to complementary DNA. All three derivatives responded to hybridization by the “turn-on” of fluorescence intensity by ca. 3-to-4 fold and may find use as probes for complementary DNA sequences.
Highlights
Since the 1980s, much effort has been devoted to exploiting fluorescence techniques in the detection and study of nucleic acids
Molecules 2020, 25, x FOR PEER REVIEW. Such as the nucleobase—with a fluorophore, or by appending a chromophore to the nucleobase or sugar-phosphate backbone [3].aAn especially fruitful approach has been to expand such as the nucleobase—with fluorophore, or by appending a chromophore to the nucleobase by or ring fusion or tobackbone extend the through ethylene ethyne bridgethe and/or by direct sugar-phosphate
In order oftoQuinazolinone-Based examine the effect Uracil of electron-withdrawing and electron-donating groups on the Scaffolds fluorescent properties of dihydroquinazolinone and quinazolinone compounds, methoxy- and Substituted quinazolines have been synthesized a numberfrom of methods, including the nitro-substituted
Summary
Since the 1980s, much effort has been devoted to exploiting fluorescence techniques in the detection and study of nucleic acids. Rotor properties that nucleobases butbehave tonucleic be fluorescent and possess molecular acid structure Selected examples of(c), uracil nucleobase (a) structural modifications: ring fusion. 1.1.Selected of uracil nucleobase (a)and structural modifications: ring (b), extension phenyl. Peptide nucleic acid (PNA) is an oligonucleotide analog capable of forming highly stable combination ofcombination high affinity high selectivity [9]attractive that enable itsthat useofenable as a probe molecule [10]. Numerous modified nucleobases have been incorporated into PNA [11]; two notable each involving multi-step ring construction syntheses Phenylpyrrolocytosine [13],analogs each involving multi-step ring construction syntheses (Figureand brightly fluorescent (PhpC). 2. Generic structure of peptide nucleic oligomer (PNA, left) and two examples of fluorescent nucleobases. 2rapid preparation and evaluation of a selection of substituted quinazolinone-uracil derivatives. Results and evaluation of a selection of substituted quinazolinone-uracil derivatives
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