Influence of bromoethyl group on biological activity of 5-fluorouracil prodrug: Insights from X-ray crystallography and molecular docking

Li, Xian-Chuan; Liu, Kuan‐Guan; Qin, Da-An; Cheng, Chen-Chen; Chen, Bing-Xiong; Hu, Mao‐Lin

doi:10.1016/j.molstruc.2012.05.070

Cited by 10 publications

(3 citation statements)

References 34 publications

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“…The lipophilicity of the fluorinated chemotherapeutic 5-fluorouracil was also measured by this procedure, giving a log D 7.4 value of −0.88. This is in close agreement with the reported log P value of −0.79, demonstrating that our protocol gives values that are relevant for comparison to other literature studies of drug lipophilicity.…”

Section: Resultssupporting

confidence: 91%

CF₃ Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

et al. 2016

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The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF3 groups also provided a spectroscopic handle for (19)F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF3-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient D at pH 7.4 (log D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using (19)F NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. (19)F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF3 groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF3 functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes.

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Section: Resultssupporting

confidence: 91%

CF₃ Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

et al. 2016

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“…The partitioning of 5-fluorouracil, a chemotherapeutic, was also evaluated using the method as described above, resulting in a log D 7.4 of −0.75. This is in good agreement with the previously reported log P of −0.79, thereby validating our method for determining the partitioning of the prepared Ru complexes.…”

Section: Resultssupporting

confidence: 92%

Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy

et al. 2021

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Alzheimer’s disease (AD) is the most common form of dementia, where one of the pathological hallmarks of AD is extracellular protein deposits, the primary component of which is the peptide amyloid-β (Aβ). Recently, the soluble form of Aβ has been recognized as the primary neurotoxic species, making it an important target for therapeutic development. Metal-based drugs are promising candidates to target Aβ, as the interactions with the peptide can be tuned by ligand design. In the current study, 11 ruthenium complexes containing pyridine-based ligands were prepared, where the functional groups at the para position on the coordinated pyridine ligand were varied to determine structure–activity relationships. Overall, the complexes with terminal primary amines had the greatest impact on modulating the aggregation of Aβ and diminishing its cytotoxicity. These results identify the importance of specific intermolecular interactions and are critical in the advancement of metal-based drugs for AD therapy.

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“…The binding constant of compound I was about 2.1 times larger than that of compound II, which indicated that the CT-DNA-binding strength of compound I was stronger than that of compound II. A stronger bonding indicated a more stable combination with CT-DNA and thus a better anticancer activity [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Two Half-Sandwiched Ruthenium (II) Compounds Containing 5-Fluorouracil Derivatives: Synthesis and Study of DNA Intercalation

Hou

Qin

et al. 2015

PLoS ONE

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Two novel coordination compounds of half-sandwiched ruthenium(II) containing 2-(5-fluorouracil)-yl-N-(pyridyl)-acetamide were synthesized, and their intercalation binding modes with calf thymus DNA were revealed by hyperchromism of ultraviolet-visible spectroscopy; the binding constants were determined according to a Langmuir adsorption equation that was deduced on the base of careful cyclic voltammetry measurements. The two compounds exhibited DNA intercalation binding activities with the binding constants of 1.13×106 M-1 and 5.35 ×105 M-1, respectively.

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Influence of bromoethyl group on biological activity of 5-fluorouracil prodrug: Insights from X-ray crystallography and molecular docking

Cited by 10 publications

References 34 publications

CF₃ Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

CF₃ Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy

Two Half-Sandwiched Ruthenium (II) Compounds Containing 5-Fluorouracil Derivatives: Synthesis and Study of DNA Intercalation

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Influence of bromoethyl group on biological activity of 5-fluorouracil prodrug: Insights from X-ray crystallography and molecular docking

Cited by 10 publications

References 34 publications

CF3 Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

CF3 Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy

Two Half-Sandwiched Ruthenium (II) Compounds Containing 5-Fluorouracil Derivatives: Synthesis and Study of DNA Intercalation

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CF₃ Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity

CF₃ Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity