Browsing by Author "Albader, Zainab"

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RECENT ADVANCES IN HETARYNE CHEMISTRY. EFFORTS TOWARD THE DEVELOPMENT OF A SINGLE PLATFORM FOR THE GENERATION OF 4,5-, 5,6-, AND 6,7-INDOLE ARYNES.
(University of Missouri-Kansas City, 2017) Albader, Zainab; Buszek, Keith
In the beginning of 2007, indole arynes and their cycloaddition chemistry were discovered by Buszek laboratories. Since then, indole arynes and their cycloaddition chemistry have demonstrated their value in the construction of biologically active natural products, such as trikentrins and herbindoles. In addition to the tremendous value of indole aryne cycloaddition chemistry in natural products total synthesis, this chemistry has successfully contributed to library development and drug discovery fields. Taking advantage of the relative electronegativity of fluorine atoms, we proposed four polyfluoroindole scaffolds that could potentially generate the all three indole arynes, namely, 4,5-, 5,6-, and 6,7-indole arynes, from a single platform through a combination of dehydrohalogenation and metal halogen exchange chemistry. In these efforts, a practical and efficient synthetic scheme was constructed via the Fischer indole reaction in order to design the four trifluoroindoles from the corresponding trifluoroanilines - a single platform to generate the three indole arynes. This efficient Fischer indole synthetic scheme was used after earlier attempts with a previous and longer synthetic route to produce 4,6,7-trifluoro-1H-indole from 2,4,5-trifluoroaniline was unsuccessful. In spite of the fact that we were not able to obtain the desired compound through this previous synthesis, unexpected results were produced (i.e., diazo-oxides compounds). The four trifluoroindole systems, namely, 4,5,6-trifluoro-3-phenyl-1H-indole, 4,5,7- trifluoro-3-phenyl-1H-indole, 4,6,7-trifluoro-3-phenyl-1H-indole, and 5,6,7- trifluoro-3-phenyl-1H-indole, have now been synthesized via the Fischer indole reaction from the commercially available triflouroanilines in two-step synthesis. Calculated acidities of the four trifluoroindole systems were performed in the gas phase, which indicated the possibility of generation indole arynes from these scaffolds. By comparing proton chemical shifts of trifluoroindole and tribromoindole sets to indole itself, proton chemical shifts of trifluoroindole scaffolds shifted upfield whereas proton chemical shifts of tribromoindole shifted further downfield. Interestingly, this can indicate that in trifluoroindole systems, fluorine atoms shield the protons whereas in tribromoindole systems, bromine atoms deshield the protons. Two systems namely, 4,5,6-trifluoro-1-methyl-3-phenyl-1H-indole and 5,6-difluoro-1-R-3-phenyl-1H-indole were proposed as a potential “universal” indole aryne generating platform.
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Targeting non-conventional quadruplex DNA structures with metal complexes
(Imperial College London, 2024) Albader, Zainab; Vilar, Ramon
Guanine quadruplexes are tetra-stranded DNA secondary structures that fold in this way due to the ability of guanines to form non-canonical hydrogen bonds. Gquadruplexes (G4s) are present in significant biological regions in the genome of both eukaryotes and prokaryotes. Because of this, G-quadruplexes have attracted great attention as a novel therapeutic strategy in cancer, pathogenic and neurodegenerative diseases. Stabilization of G-quadruplexes via small molecules including cationic heterocyclic molecules and metal complexes can be a potential therapeutic approach to overcome current challenges, such as antimicrobial resistance. According to G4LDB database, many G4 ligands (over 4000 ligands) have been synthesized and studied. However, there is still a lack of G4 ligands to target specific sequences, particularly those that lead to non-conventional G4 structures. One example of a non-conventional G4 is the hybrid quadruplex-duplex in LTR-III promoter in the HIV-1 virus. It has been found that stabilization of LTR-III with small molecules can inhibit the viral activity. In this research, I aim to selectively stabilize the hybrid quadruplex-duplex sequences followed by biophysical characterization to study the effect of hybrid quadruplexduplex ligands on the unusual hybrid G-quadruplex structures including LTR-III and MYT1L sequences. To achieve this aim, I synthesized hybrid metal salphen complexes with different backbones and geometries. Biophysical studies were conducted to assess the thermal stabilities of G4 sequences using FRET melting and FRET competition assays. These studies have shown that substituted metal salphen complexes can selectively bind to the hybrid sequences with higher melting temperatures as compared to the traditional G4s. Further analysis was carried out to understand the effect of binding on the G4 topology using CD spectroscopy. In addition, Fluorescence Indicator Displacement (FID) assays and fluorescence spectroscopy were used to gain further insight into the interactions of the compounds and the non-conventional G4s.
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