1948

DOI: 10.1039/jr9480001759

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356. Synthetic antimalarials. Part XXXI. 2-p-chloroanilino-4-β-diethylaminoethylaminoquinazolines containing various substituents in the quinazoline nucleus

F. H. S. Curd¹,

J. K. Landquist²,

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Materials and Experimental Methodology1

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7-dichloro-4-(isopropylthio)quinazoline (1)1

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1949

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Cited by 35 publications

(13 citation statements)

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“…The NdU was incorporated into five separate oligonucleotides to replace each of the five thymidines present in the Py39WT sequence one at a time. The NdU extinction coefficient of 49 800 M −1 cm −1 was used in calculations for each substituted oligomer 66. The extinction coefficient for each oligomer, 10T, 20T, 21T, 24T, and 39T, was 328 680 M −1 cm −1 .…”

Section: Materials and Experimental Methodologymentioning

confidence: 99%

The i-Motif in the bcl-2 P1 Promoter Forms an Unexpectedly Stable Structure with a Unique 8:5:7 Loop Folding Pattern

¹

,

²

,

³

et al. 2009

J. Am. Chem. Soc.

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Transcriptional regulation of the bcl-2 proto-oncogene is highly complex, with the majority of transcription driven by the P1 promoter site and the interaction of multiple regulatory proteins. A guanine-and cytosine-rich (GC-rich) region directly upstream of the P1 site has been shown to be integral to bcl-2 promoter activity, as deletion or mutation of this region significantly increases transcription. This GC-rich element consists of six contiguous runs of guanines and cytosines that have the potential to adopt DNA secondary structures, the G-quadruplex and i-motif, respectively. Our laboratory has previously demonstrated that the polypurine-rich strand of the bcl-2 promoter can form a mixture of three different G-quadruplex structures. In this current study, we demonstrate that the complementary polypyrimidine-rich strand is capable of forming one major intramolecular imotif DNA secondary structure with a transition pH of 6.6. Characterization of the i-motif folding pattern using mutational studies coupled with circular dichroic spectra and thermal stability analyses revealed an 8:5:7 loop conformation as the predominant structure at pH 6.1. The folding pattern was further supported by chemical footprinting with bromine. In addition, a novel assay involving the sequential incorporation of a fluorescent thymine analog at each thymine position provided evidence of a capping structure within the top loop region of the i-motif. The potential of the GC-rich element within the bcl-2 promoter region to form DNA secondary structures suggests that the transition from the B-DNA to non-B-DNA conformation may play an important role in bcl-2 transcriptional regulation. Furthermore, the two adjacent large lateral loops in the i-motif structure provide an unexpected opportunity for protein and small molecule recognition.

“…The NdU was incorporated into five separate oligonucleotides to replace each of the five thymidines present in the Py39WT sequence one at a time. The NdU extinction coefficient of 49 800 M −1 cm −1 was used in calculations for each substituted oligomer 66. The extinction coefficient for each oligomer, 10T, 20T, 21T, 24T, and 39T, was 328 680 M −1 cm −1 .…”

Section: Materials and Experimental Methodologymentioning

confidence: 99%

The i-Motif in the bcl-2 P1 Promoter Forms an Unexpectedly Stable Structure with a Unique 8:5:7 Loop Folding Pattern

¹

,

²

,

³

et al. 2009

J. Am. Chem. Soc.

View full text Add to dashboard Cite

Transcriptional regulation of the bcl-2 proto-oncogene is highly complex, with the majority of transcription driven by the P1 promoter site and the interaction of multiple regulatory proteins. A guanine-and cytosine-rich (GC-rich) region directly upstream of the P1 site has been shown to be integral to bcl-2 promoter activity, as deletion or mutation of this region significantly increases transcription. This GC-rich element consists of six contiguous runs of guanines and cytosines that have the potential to adopt DNA secondary structures, the G-quadruplex and i-motif, respectively. Our laboratory has previously demonstrated that the polypurine-rich strand of the bcl-2 promoter can form a mixture of three different G-quadruplex structures. In this current study, we demonstrate that the complementary polypyrimidine-rich strand is capable of forming one major intramolecular imotif DNA secondary structure with a transition pH of 6.6. Characterization of the i-motif folding pattern using mutational studies coupled with circular dichroic spectra and thermal stability analyses revealed an 8:5:7 loop conformation as the predominant structure at pH 6.1. The folding pattern was further supported by chemical footprinting with bromine. In addition, a novel assay involving the sequential incorporation of a fluorescent thymine analog at each thymine position provided evidence of a capping structure within the top loop region of the i-motif. The potential of the GC-rich element within the bcl-2 promoter region to form DNA secondary structures suggests that the transition from the B-DNA to non-B-DNA conformation may play an important role in bcl-2 transcriptional regulation. Furthermore, the two adjacent large lateral loops in the i-motif structure provide an unexpected opportunity for protein and small molecule recognition.

“…1A) was synthesized according to a previously published procedure (Curd et al, 1948 the phosphoramidite derivative were obtained through a synthetic route previously used for quinazoline derivatives (Michel et al, 1995(Michel et al, , 1997. The deoxyribonucleoside of this thymine analog showed a fluorescence emission characterized by three major excitation maxima: 253, 294, and 360 nm (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Fluorescent Base Analog for Probing Triple Helix Formation

¹

,

et al. 1998

Antisense and Nucleic Acid Drug Development

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Benzo[gJquinazoline-2,4-(l//,3//)-dione (BgQ), a fluorescent thymine analog, was incorporated into an oligopyrimidine (III) able to give rise to a triple-stranded structure by clamping a purine 11-mer (I). The formation of the 1-111 complex resulted in both a shift of the fluorescence emission maximum and a decreased fluorescence intensity. No such variations were observed on the formation of a Watson-Crick duplex between I and the complementary strand in which a T residue was substituted for BgQ. Therefore, the fluorescence emission of BgQ can be used to selectively monitor the formation of triple helices.

“…To a solution of 2,4,7-trichloroquinazoline14 (0.300 g, 1.28 mmol) in freshly distilled and degassed THF (13.0 mL) cooled to 0 °C was added a premixed solution of i -PrSH (0.12 mL, 1.28 mmol) and NaH (0.032 g, 1.35 mmol) in THF (2.0 mL) dropwise. The mixture was stirred for 16 h, warmed to r.t., poured into ice cold H 2 O, extracted with EtOAc (5 × 25 mL), and washed with H 2 O.…”

Section: 7-dichloro-4-(isopropylthio)quinazoline (1)mentioning

confidence: 99%

“…To our knowledge, a regioselective method for the sequential polyarylation of trihalogenated quinazolines has not been disclosed. Herein, we describe a versatile new protocol for the regioselective palladium-catalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline14 with aryl- and heteroarylboronic acids.…”

mentioning

confidence: 99%

Regioselective Palladium-Catalyzed Cross-Coupling Reactions of 2,4,7-Trichloroquinazoline

Wipf¹,

2010

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The regioselective palladium-catalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline with various aryl-and heteroarylboronic acids are reported. An efficient, sequential strategy was developed that provides access to novel, functionalized heterocycles.Keywords palladium catalysis; cross-coupling; heterocycles; regioselectivity; quinazoline Palladium-catalyzed cross-coupling reactions represent a powerful method for the formation of highly substituted heterocycles. 1 The regioselective activation of polyhalogenated heteroaromatics in such reactions has been extensively studied 2 and can provide a versatile means for the synthesis of libraries containing functionalized substituents in specific positions of the heterocyclic scaffold. The quinazoline moiety is of particular importance, as it is a component of a variety of biologically active compounds, including potent tyrosine kinase inhibitors, 3 antibacterial, 4 and anticancer agents. 5 For example, trisubstituted quinazoline derivatives such as A and B have been prepared as part of a series of liver X receptor (LXR) modulators (Figure 1). 6 Quinazolines are also components of several approved drugs, including erlotinib, 7 used to treat several types of tumors, iressa, 8 an epidermal growth factor receptor inhibitor approved for the treatment of nonsmall cell lung cancer, and prazosin, 9 an α-adrenergic receptor blocker. While the regioselectivity for palladium-catalyzed alkylation, 10 alkynylation, 11 and arylation 12 of 2,4-dichloroquinazolines has been previously explored, only the alkylation 10 and alkynylation 11 of 6-bromo-2,4-dichloroquinazoline have been reported. For crosscoupling reactions employing 2,4-dichloroquinazoline, exclusive selectivity for the most electrophilic C-4 position 13 has been observed. Attempts to achieve monosubstitution with the more highly halogenated 6-bromo-2,4-dichloroquinazoline resulted in coupling at both the C-4 and C-6 positions in a ratio of 3:1, respectively. To our knowledge, a regioselective method for the sequential polyarylation of trihalogenated quinazolines has not been disclosed. Herein, we describe a versatile new protocol for the regioselective palladiumcatalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline 14 with aryl-and heteroarylboronic acids.Initially, we set out to achieve the regioselective cross-coupling of 2,4,7-trichloroquinazoline by consecutive, Suzuki cross-couplings (Scheme 1, route A). We Fax +1 (412)6240787 envisioned the first coupling to take place at the most electrophilic C-4 position, followed by substitutions at the C-2 and C-7 positions, respectively. However, coupling at C-4 proved to be low-yielding due to competitive hydrolysis at that site under the reaction conditions. In order to circumvent this problem, a new route was designed in which the C-4 position was first temporarily deactivated by a thioether, followed by a regioselective cross-coupling at C-2 (Scheme 1, route B). The C-4 position would then be functionalized via a palladiumcatalyzed, copper(I...

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