Recent advances in thymidine phosphorylase inhibitors: syntheses and prospective medicinal applications

Sajid, Muhammad Aamir; Khan, Zulfiqar Ali; Shahzad, Sohail Anjum; Naqvi, Syed Ali Raza; Usman, Muhammad; Iqbal, Ahsan

doi:10.3906/kim-1602-79

Cited by 9 publications

(3 citation statements)

References 56 publications

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“…In the current study, we decided to modify the structural framework of dihydropyridines and pyridines by introducing a range of moieties to accomplish interesting small heterocycles with a high inhibitory activity of alkaline phosphatases and cancer cell lines (HeLa and MCF-7). We have learned from our previous studies on the development of anticancer agents [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ] that the potential of inhibitory activity can be enhanced through the incorporation of bulky groups with various spacers. Furthermore, pro-apoptotic behavior and cell cycle arrests were performed to assess the anticancer potential of the synthesized compounds.…”

Section: Resultsmentioning

confidence: 99%

“…We studied the most achievable binding interactions of the most biologically potent compounds (newly synthesized) within the active site of h -TNAP using the Molecular Operating Environment (MOE) software [ 54 ]. The amino acid residues which were involved in the bonding and nonbonding interactions with ligands 4d , 4e – 4g , and 4j include Arg167, Ser93, Asp92, His154, His321, His324, and His437, which played a significant role in ligand–protein binding [ 8 , 50 ]. The co-crystallized protein structure was not available, therefore a previously reported homology model of a protein (APs enzyme) was used for this object [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis

et al. 2022

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Small molecules with nitrogen-containing scaffolds have gained much attention due to their biological importance in the development of new anticancer agents. The present paper reports the synthesis of a library of new dihydropyridine and pyridine analogs with diverse pharmacophores. All compounds were tested against the human tissue nonspecific alkaline phosphatase (h-TNAP) enzyme. Most of the compounds showed excellent enzyme inhibition against h-TNAP, having IC50 values ranging from 0.49 ± 0.025 to 8.8 ± 0.53 µM, which is multi-fold higher than that of the standard inhibitor (levamisole = 22.65 ± 1.60 µM) of the h-TNAP enzyme. Furthermore, an MTT assay was carried out to evaluate cytotoxicity against the HeLa and MCF-7 cancer cell lines. Among the analogs, the most potent dihydropyridine-based compound 4d was selected to investigate pro-apoptotic behavior. The further analysis demonstrated that compound 4d played a significant role in inducing apoptosis through multiple mechanisms, including overproduction of reactive oxygen species, mitochondrial dysfunction, DNA damaging, and arrest of the cell cycle at the G1 phase by inhibiting CDK4/6. The apoptosis-inducing effect of compound 4d was studied through staining agents, microscopic, and flow cytometry techniques. Detailed structure–activity relationship (SAR) and molecular docking studies were carried out to identify the core structural features responsible for inhibiting the enzymatic activity of the h-TNAP enzyme. Moreover, fluorescence emission studies corroborated the binding interaction of compound 4d with DNA through a fluorescence titration experiment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis

et al. 2022

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“…For a recent review see Sajid et al. 19 . In order to interact with the thymidine binding site, most of them are pyrimidine-2,4-dione derivatives.…”

Section: Introductionmentioning

confidence: 99%

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis, biological evaluation, and molecular docking study

Aknin

Bontemps

Farce

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d , 2l , 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d , 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.

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Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines

Iftikhar

Yaqoob

Tabassum

et al. 2018

Bioorganic Chemistry

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Recent advances in thymidine phosphorylase inhibitors: syntheses and prospective medicinal applications

Cited by 9 publications

References 56 publications

Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis

Design, Synthesis, and Biological Evaluation of Novel Dihydropyridine and Pyridine Analogs as Potent Human Tissue Nonspecific Alkaline Phosphatase Inhibitors with Anticancer Activity: ROS and DNA Damage-Induced Apoptosis

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis, biological evaluation, and molecular docking study

Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines

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