34 research outputs found
Template-assembled synthetic G-quartets (TASQS)
No full textFabrication of functional supramolecular structures requires a certain degree of control
which may not be achieved by relying solely on noncovalent interactions. The current study
aims to investigate the effect of a rigid cavitand template on morphology, function and stability
of lipophilic G-quadruplexes. The first Chapter of this thesis introduces different aspects of G
quadruplex chemistry and explains how these structures are particularly suited for the creation of
supramolecular architectures.
The second Chapter of this thesis presents the synthesis and self-assembly of a new class
of supramolecular architectures composed of four guanosines attached to a rigid cavitand
template. These structures, named template-assembled synthetic G-quartets (TASQs), were
synthesized via the “click” reaction and manifest an ordered topology dictated by the template.
The lipophilic TASQs were found to self-associate spontaneously to form a singular basket-like
structure in chloroform. Moreover, it was found that TASQs form cation-free G-quartets which
exhibit remarkable stability under this condition.
The third Chapter of this thesis describes the preparation, characterization and solution
study of the cation-bound complexes TASQNa⁺, TASQK⁺, TASQCs⁺, and TASQSr²⁺.
Cations play a major role in controlling the morphology and stability of G-quadruplexes. The
analysis of the cation-specific structures of TASQs reveals the formation of a monomeric G
quartet for Na⁺ and Sr²⁺,a dimeric system for Cs⁺ and a mixture of monomers and dimers for K⁺.
The factors governing the formation of these structures were evaluated, the selectivities of
TASQs for cations were determined, and the cation-dependent structural transformations were
studied.
The fourth Chapter describes the efforts towards synthesizing a hydrophilic TASQ via
the “click” reaction. The following steps have been taken: 1) a water-soluble cavitand has been
successfully synthesized and characterized, which can potentially serve as a hydrophilic
template, and 2) two oligonucleotides have been appropriately functionalized and preliminary
coupling reactions were attempted. The next phases of this research along with potential future
directions are discussed in Chapter five.Science, Faculty ofChemistry, Department ofGraduat
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Abstract 3180: Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma
No full textAbstract Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, with a poor prognosis that highlights a dire clinical need for innovative therapeutic interventions. Despite significant advances in diagnoses and multimodality therapies, the overall prognosis for patients with GBM remains poor, with a median survival time of 15-18 months. Therefore, there is an unmet medical need to develop alternative treatment strategies to improve clinical outcomes. Dysregulation of post-transcriptional control and translational machinery have been implicated in malignant tumor development. Cytoplasmic polyadenylation element binding proteins (CPEB1-CPEB4) are RNA-binding proteins that regulate poly(A) tail elongation of target mRNAs and subsequently contribute to phenotypic changes in cancer cells. Notably, a self-cleaving ribozyme was identified in the CPEB3 gene, but its role in cancer is wholly unexplored. Considering the role of CPEB3 as a tumor suppressor gene and the promotion of cancer progression through the downregulation of CPEB3, our hypothesis is that the CPEB3 ribozyme regulates CPEB3 expression, and its activity contributes to the progression of tumors. Using antisense oligonucleotides (ASOs) as an approach, we demonstrated that inhibition of CPEB3 ribozyme resulted in an increase of CPEB3 mRNA and protein expression. Blocking the CPEB3 ribozyme led to a significant reduction in cell proliferation, migration, and invasion in GBM cell lines. Gene set enrichment analysis (GSEA) revealed the downregulation of epithelial-mesenchymal transition (EMT), angiogenesis, and hypoxia gene sets in GBM cells treated with ASO compared to Ctrl-ASO. We further measured VEGFA mRNA and protein expression and found that ASO-treated GBM cells secreted significantly less VEGF in conditioned media. Inhibition of the CPEB3 ribozyme also mitigated the EMT process in GBM cells. Subsequently, ASO strategies were applied to patient-derived glioma stem cells (GSCs), representing a clinically relevant model for pre-clinical therapeutic intervention. We found that treatment of CPEB3 ribozyme ASO up-regulated CPEB3 mRNA and inhibited cell proliferation in GSCs. Furthermore, the combination of ASO and temozolomide chemotherapy exhibited a more pronounced decrease in GSCs proliferation compared to individual treatment alone. Collectively, this study highlights the significance of the CPEB3 ribozyme in GBM and explores therapeutic approaches focused on targeting CPEB3 in cancer. Citation Format: Claire Chen, Eric Wang, Lily Tong, Mehran Nikan, Daniela A. Bota, Claudia Benavente, Andrej Luptak. Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3180
Cation-Complexation Behavior of Template-Assembled Synthetic G-Quartets
No full textWe report the preparation and solution study of a set of template-assembled synthetic G-quartets (TASQs) bound to different cations. These G-quartet baskets effectively extract cations of different sizes and valencies. They form isolated G-quartets with small cations such as Na+ and Sr2+, and dimeric assemblies with larger cations such as Cs+. Their structures were determined by using 1H NMR spectroscopy, and their sizes were evaluated by using a series of pulsed-field gradient NMR experiments. The effect of anion has been studied, and the cation selectivities have been investigated by a series of competition experiments
Modeling high temperature deformation characteristics of AA7020 aluminum alloy using substructure-based constitutive equations and mesh-free approximation method
No full textThis research was aimed to assess the potential of a radial basis function (RBF) approximation method against the dislocation substructure-based constitutive model in predicting high-temperature deformation behavior of the AA7020 aluminum alloy. Hot compression tests were performed over a range of strain rate of 0.1–100 s−1 and a range of temperature of 350–500 °C up to a strain of 0.6. The hot deformation behavior of the alloy was first described by a substructure kinetic-based constitutive equation, with the effects of strain, strain rate and temperature together with dynamic recovery parameters taken into consideration. A RBF approximation method was then developed to model the flow behavior of the material. The RBF model, as a kind of novel mesh-free function estimation approach, was trained and tested with the obtained datasets from the hot compression tests. The performance of the developed analytical and neural computational models was evaluated using statistical criteria. The results showed that the RBF model was more proficient and accurate in predicting the hot deformation behavior of this aluminum alloy than the substructure-based constitutive model.Accepted Author ManuscriptBiomaterials & Tissue Biomechanic
Development of Novel Class of Therapeutic Oligonucleotides Based on Small Molecule Screening
No full textAbstract of poster presented at the 2014 UMass Center for Clinical and Translational Science Research Retreat, held on May 20, 2014 at the University of Massachusetts Medical School, Worcester, Mass.Highly inefficient transit of oligonucleotides from outside cells to the intracellular compartments where functional activity of oligonucleotides takes place is the most serious limitation to the practical realization of a full potential of oligonucleotide-based therapies. Several classes of oligonucleotide therapeutics (ONT), including antisense oligonucleotides (ASO), hydrophobically modified siRNAs (hsiRNA), GalNAc-conjugated siRNAs, and LNP-formulated siRNAs have validated biological efficacy and are in clinic. In all cases, the fraction of oligonucleotides reaching the intended place of biological function is surprisingly low, with the majority of molecules being trapped in wrong cellular compartments, resulting in low efficiency and clinically limiting toxicity. We have recently completed a cell-based screen using the LOPAC library and identified a panel of small molecules that alter cellular localization and dramatically enhance the efficacy of hydrophobically modified siRNAs (hsiRNAs) developed previously [4] (Navaroli et al 2013). In the presence of top two hits (Guanabenz and Phenamil), we have observed a dose-dependent enhancement of oligonucleotide efficacy, with both a significant increase in cellular uptake and decrease in EC50 values. Use of small molecules as enhancers and modulators of oligonucleotide therapeutic efficacy is a new paradigm in formulation development with wide implications on compounds in clinic and future developments
An Acetylene‐Bridged 6,8‐Purine Dimer as a Fluorescent Switch‐On Probe for Parallel G‐Quadruplexes
No full textAbstract 3180: Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma
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