Lowering the overall charge on TMPyP4 improves its selectivity for G-quadruplex DNA

Ruan, Thomas; Davis, Supriya J.; Powell, Barrett M.; Harbeck, Cole P.; Habdas, Jan; Habdas, Piotr; Yatsunyk, Liliya A.

doi:10.1016/j.biochi.2016.11.003

Cited by 33 publications

(25 citation statements)

References 65 publications

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“…Ionic strength increase suppresses strong, but nonspecific electrostatic interactions, resulting in the increase of ligand selectivity for G4, however, this effect is obviously associated with a decrease of binding affinity (Table 1). These data are in line with a recent finding that lowering the total charge on TMPyP decreases the affinity, but increases the selectivity to G4 vs. dsDNA [48].…”

Section: Ligand Affinity and Selectivitysupporting

confidence: 93%

Interaction of cationic porphyrin-imidazophenazine conjugates with DNA quadruplex: FID assay and quantum-chemical modeling

et al. 2018

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To study the efficiency of tricationic porphyrin-imidazo[4,5-b]phenazine conjugate and its Zn(II) and Mn(III) complexes as G-quadruplex (G4) DNA ligands. Methods. FID (Fluorescent Intercalator Displacement) assay was used to evaluate the affinity of compounds for a model duplex and Tel22 quadruplex DNA at various ionic strengths. Molecular modeling of the conjugate interaction with G4 DNA was performed using the Density Functional Theory (DFT) calculations with M06-2X functional and 6-31G(d) basis set. Guanine octet stabilized with K + ion was used as a G4 model. Results. DC 50 values and dissociation constants were determined for the complexes of three conjugates with duplex and quadruplex DNA. The structures and energetic parameters of G-octet complexes with Zn-metalated conjugate were obtained. Conclusions. All complexes have a strong affinity to the Tel22 quadruplex. The increase of ionic strength results in an increase in selectivity for quadruplex over duplex DNA and the decrease of binding affinity of the ligands. The structure of ligand-G4 complexes is determined by stacking interaction of porphyrin fragment with G-quartet, rather than an intercalative binging of the ligand.

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Section: Ligand Affinity and Selectivitysupporting

confidence: 93%

Interaction of cationic porphyrin-imidazophenazine conjugates with DNA quadruplex: FID assay and quantum-chemical modeling

et al. 2018

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“…For instance, TMPyP4, a typical cationic G4 stabilizer, loses its telomerase inhibitory activity under excessive dsDNA condition due to non-specific binding. 19,20 Although telomestatin as a natural compound binds to telomere G4 with high selectivity, the low solubility limits its pharmacological effect. 21,22 Interestingly, the negatively charged phthalocyanine APC ( Figure 1A) binds to telomere hybrid G4s with advanced selectivity and good solubility, leading to an efficient inhibition of telomerase activity even in the presence of excessive dsDNA.…”

Section: Introductionmentioning

confidence: 99%

Retracted: Molecular insight into the selective binding between human telomere G‐quadruplex and a negatively charged stabilizer

Wang

et al. 2020

Clin Exp Pharma Physio

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The single‐strand human telomere overhang forms intramolecular high‐order structures named G‐quadruplex (G4) under physiological conditions. Telomere G4 stabilization prevents telomere lengthening by telomerase in cancer cells representing a promising strategy in cancer therapy. Using molecular docking and molecular dynamics (MD) simulations, specific binding of the anionic phthalocyanine 3,4ʹ,4ʹʹ,4ʹʹʹ‐tetrasulfonic acid (APC) to the human hybrid (3 + 1) G4s was investigated at the atomic level. We found that APC preferred the end‐stacking binding with the telomere hybrid type II (hybrid‐II) G4 as compared to the groove binding with the hybrid type I (hybrid‐I) G4 remarkable stabilizing effect and more favourable binding free energies. Analysis of non‐covalent interaction and decomposition of the binding free energy revealed that van der Waals interaction played a leading role in the binding of APC and telomere hybrid G4s. These findings provide evidence for the first time to shed light on the designs of selective telomere G4 stabilizers.

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“…Photosensitizer Pd(T4) has demonstrated elevated singlet oxygen production post-illumination compared to its base conjugate TMPyP [27], resulting in photodynamic inactivation of bacteria such as methicillin-resistant Staphylococcus aureus and Escherichia coli [27]. TMPyP4, the base conjugate, has exhibited a strong affinity for G4 quadruplexes [28][29][30], as well as other macromolecules [31,32]. Our study assessed the oncolytic potential of Pd(T4) when used in a photodynamic system as a primary or potential combinatorial component with 5-ALA and blue light against cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Metalloporphyrin Pd(T4) Exhibits Oncolytic Activity and Cumulative Effects with 5-ALA Photodynamic Treatment against C918 Cells

Leviskas

Vályi-Nagy

Munirathinam

et al. 2020

IJMS

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Photodynamic therapy is a non-invasive method where light activates a photosensitizer bound to cancer cells, generating reactive oxygen species and resulting in cell death. This study assessed the oncolytic potential of photodynamic therapy, comparing European Medicines Agency and United States Food and Drug Administration-approved 5-aminolevulinic acid (5-ALA) to a metalloporphyrin, Pd(T4), against a highly invasive uveal melanoma cell line (C918) in two- and three-dimensional models in vitro. Epithelial monolayer studies displayed strong oncolytic effects (>70%) when utilizing Pd(T4) at a fraction of the concentration, and reduced pre-illumination time compared to 5-ALA post-405 nm irradiance. When analyzed at sub-optimal concentrations, application of Pd(T4) and 5-ALA with 405 nm displayed cumulative effects. Lethality from Pd(T4)-photodynamic therapy was maintained within a three-dimensional model, including the more resilient vasculogenic mimicry-forming cells, though at lower rates. At high concentrations, modality of cell death exhibited necrosis partially dependent on reactive oxygen species. However, sub-optimal concentrations of photosensitizer exhibited an apoptotic protein expression profile characterized by increased Bax/Bcl-2 ratio and endoplasmic stress-related proteins, along with downregulation of apoptotic inhibitors CIAP-1 and -2. Together, our results indicate Pd(T4) as a strong photosensitizer alone and in combination with 5-ALA against C918 cells.

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Lowering the overall charge on TMPyP4 improves its selectivity for G-quadruplex DNA

Cited by 33 publications

References 65 publications

Interaction of cationic porphyrin-imidazophenazine conjugates with DNA quadruplex: FID assay and quantum-chemical modeling

Interaction of cationic porphyrin-imidazophenazine conjugates with DNA quadruplex: FID assay and quantum-chemical modeling

Retracted: Molecular insight into the selective binding between human telomere G‐quadruplex and a negatively charged stabilizer

Metalloporphyrin Pd(T4) Exhibits Oncolytic Activity and Cumulative Effects with 5-ALA Photodynamic Treatment against C918 Cells

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